Ccr4 antagonist and medical use thereof

ABSTRACT

A compound of formula (I) or a salt thereof, and medical use thereof (the symbols in the formula are as described in the specification).  
                 
The compound of formula (I) has CCR4 antagonistic activity, and therefore is useful as a preventive and/or therapeutic agent for diseases associated with CCR4, i.e., CCR4-mediated diseases such as inflammatory and/or allergic diseases [e.g., systemic inflammatory response syndrome (SIRS), anaphylaxis or anaphylaxis-like reaction, allergic vasculitis, reject reaction for graft organ, hepatitis, nephritis, nephrosis, pancreatitis, rhinitis, arthritis, inflammatory ocular diseases, inflammatory bowel diseases, diseases in cerebro and/or circulatory system, respiratory diseases, dermatic diseases, autoimmune diseases, etc.], and the like.

TECHNICAL FIELD

The present invention relates to a compound having CCR4 antagonisticactivity which is useful as a medicament, a method for producing thesame, and use thereof.

BACKGROUND ART

Chemokine is known as a basic protein having endogenous leukocytechemotactic and activating activities and strong heparin-bindingabilities. At present, it is considered that chemokine is related to notonly the control of infiltration of specific leukocyte at the time ofinflammations and immune responses but also the development and homingof lymphocyte under physiological conditions and migration of hemocyteprecursor cells and somatic cells.

Differentiation, proliferation and cell death of hemocytes arecontrolled by various types of cytokine. In the living body,inflammations are found locally and differentiation, maturation and thelike of lymphocytes are carried out at certain specific sites. That is,various necessary cells migrate into certain specified sites andaccumulate therein to cause a series of inflammations and immuneresponses. Accordingly, migration of cells is also an indispensablephenomenon to lead to the immune system in addition to differentiation,proliferation and death of cells.

Migration of hemocytes in the living body starts firstly in thedevelopment stage by the shift of hematopoiesis started in the AGMregion into permanent hematopoiesis in bone marrow via fetal liver.Furthermore, precursor cells of T cells and thymus dendritic cellsmigrate from the fetal liver into the bone marrow and then into thethymus gland and cytodifferentiate under thymus environment. The T cellwhich is subjected to clone selection migrates into secondary lymphoidtissues and takes part in an immune response in the periphery. TheLangerhans's cell of the skin activated and differentiated by capturingan antigen migrates into the T cell region of a topical lymph node andactivates naive T cell therein as a dendritic cell. The memory T cellagain performs its homing again into the lymph node via lymphatic andblood vessels. Also, B cell, T cell in the intestinal epithelium, γδ Tcell, NKT cell and dendritic cell migrate from bone marrow withoutpassing through the thymus gland and differentiate to take part in animmune response.

Chemokine is deeply related to the migration of these various cells. Forexample, CCR4 which is a receptor for MDC and TARC is expressed in Th2cell (see J. Immunol., 161, 5111 (1998)), and is known to play animportant role in the migration of Th2 cell into topical sites whereimmune and inflammatory responses related to the Th2 cell is induced. Ina mouse OVA-induced airway hypersensitivity model, an anti-MDC antibodysuppressed the number of eosinophils accumulated in the lunginterstitium, and suppressed airway hypersensitivity (see J. Immunol.,163, 403 (1999)). In a mouse OVA-induced airway hypersensitivity model,anti-TARC antibody suppressed infiltration of eosinophils andlymphocytes into the airway as well as airway hypersensitivity (see J.Immunol, 166, 2055 (2001)). In the investigation with Nc/Nga mouse, itwas recognized that amounts of TARC and MDC have increased in the atopicdermatitis-like lesion site (see J. Clin. Invest., 104, 1097 (1999)).For CCR4 relation to human pathologic conditions, the number of CCR4positive memory-T lymphocyte in peripheral blood increased depending onseverity of dermatitis (see J. Allergy Clin. Immunol., 107, 353 (2001)),and the amount of TARC in the serum was also correlated to the severityin the atopic dermatitis patients (see J. Allergy Clin. Immunol., 107,535 (2001)). The amount of TARC in the serum and the induced sputum alsoincreased in the asthma patients (see Allergy, 57, 173 (2002)). MDCconcentration in the blood was high in Th2 diseases such as atopicdermatitis and Sezary syndrome (see Eur. J. Immunol., 30, 201 (2000)).

There have been many reports suggesting correlation with otherinflammatory diseases than allergic diseases, and CCR4 positive cell wasaccumulated selectively in the affected site of Lupus nephritis (seeArthritis Rheum., 46, 735 (2002)). Expression of TARC and MDC was highin the affected site of Crohn's disease (see Eur. Cytokine Netw., 12,468 (2001)). CCR4 expression rose in the peripheral blood CD4 positivecells of systemic lupus erythematodes patients as compared with healthypersons (see J. Leuko., Biol., 70, 749 (2001)).

Furthermore, it has been known that chemokine play various roles inimmune responses in addition to the migration of various cells. In theinvestigation with CCR4 deficient mouse, it was recognized thatlethality by high dose LPS shock reduced as compared with wild type, andfurther, amounts of TNFα, IL-1β and MIP-1α also reduced in the bloodafter administration of LPS. Furthermore, in a rat fulminant hepatitismodel (P.acnes+LPS), an anti-TARC antibody suppressed increase of theamount of ALT in the blood and increase of the expression amounts ofTNFα and FasL in the liver and also improved lethality of the rats (seeJ. Clin. Invest., 102, 1933 (1998)). It was shown that CCR4 contributesto the binding of activated T cells and dendritic cells (see J.Immunol., 167, 4791 (2001)). Furthermore, TARC and MDC caused plateletaggregation mediated by CCR4 (see Thrombosis Research, 101, 279 (2001)),which is one of various physiological activities of chemokines andchemokine receptors.

Based on the above, chemokines and chemokine receptors are greatlyrelated to the control of inflammation and/or immune responses through amechanism in which they are expressed at certain specified periods invariously specific cells and its effector cells are accumulated in aregion where chemokine is produced.

As described above, CCR4 antagonists have TNFα regulatory activity andinhibitory activity for the functions of the effector cells in additionto CCR4 antagonistic activity. Therefore, it is considered to use CCR4antagonist as a preventive and/or therapeutic agent for inflammatoryand/or allergic diseases [for example, systemic inflammatory responsesyndrome (SIRS), anaphylaxis or anaphylactoid reaction, allergicvasculitis, transplant rejection reaction, hepatitis, nephritis,nephropathy, pancreatitis, rhinitis, arthritis, inflammatory oculardiseases (e.g., conjunctivitis, etc.), inflammatory bowel diseases(e.g., ulcerative colitis, Crohn's disease, eosinophilicgastroenteropathy, etc.), diseases in cerebro and/or circulatory system(e.g., arteriosclerosis, thrombosis, ischemic/reperfusion disorders,restenosis, infarction, etc.), respiratory diseases (e.g., acuterespiratory distress syndrome (ARDS), asthma, allergic broncho-pulmonaryaspergillosis, etc.), dermatosis (e.g., dermatitis such as atopicdermatitis, psoriasis, contact dermatitis, eczema, urticaria andpruritus, and the like), autoimmune diseases (e.g., multiple sclerosis,chronic articular rheumatism, systemic lupus erythematodes, Type Idiabetes mellitus, glomerular nephritis, Sjoegren's syndrome, etc.), andthe like], metabolism and/or endocrine system diseases (e.g., diabetesmellitus, etc.), cancer diseases [for example, malignant neoplasm suchas leukemia, cancer and cancer metastasis, etc.), and the like],infections [for example, viral diseases (e.g., acquired immunodeficiencysyndrome, SARS, etc.), and the like], and the like.

On the other hand, it was described that a compound of formula (X):J^(X)-M^(X)  (X)wherein J^(X) represents an aromatic moiety; and M^(X) represents amoiety interacting with a G protein-coupled receptor. It was alsodescribed that as a more specific compound, a compound of formula (X-I):A^(X)-L^(1X)-B^(X)-L^(2X)-E^(X)  (X-1)wherein A^(X) represents alkyl, aryl or heteroaryl which may besubstituted, etc.; L^(1X) represents O, S, CHOH, O(CH₂)_(nx), etc.; nXrepresents 0, 1, 2 or 3; B^(X) represents an 5- to 7-membered aromaticring which may be substituted and may have 0 to 3 hetero atoms; L^(2X)represents CH₂C═O, NHC═O, OC═O, etc.; and E^(X) represents a moietyinteracting with a G protein-coupled receptor, with the proviso that thedefinitions of each symbol are partially excerpted, binds to a Gprotein-coupled receptor (e.g., WO00/46203).

Furthermore, it was described that a compound of formula (Y):

wherein A^(Y) represents

etc.; R^(3Y), R^(3aY) and R^(3bY) each independently representshydrogen, alkyl, etc.; oY represents 1 or 2; R^(9Y) represents hydrogenor alkyl; R^(1Y) represents alkoxy, halogen,

etc.; R^(2Y) represents CF₃, —NR^(10Y)R^(11Y), etc.; R^(10Y) representshydrogen, alkyl or aralkyl; R^(11Y) represents

etc.; nY represents 0 or 1; R^(5Y) and R^(6Y) each independentlyrepresents hydrogen, alkyl, cycloalkyl, etc., with the proviso that thedefinitions of each symbol are partially excerpted, is useful as an IL-8receptor (CXCR1 and CXCR2) agonist (e.g., WO99/42463).

Furthermore, so far, several low molecular compounds have been reportedto have CCR4 antagonistic activity (e.g., WO02/30357, WO02/30358 andWO02/94264).

However, until now, no pyrazine derivatives having CCR4 antagonisticactivity have been reported.

DISCLOSURE OF THE INVENTION

A preventive and/or therapeutic agent for asthma, atopic dermatitis andthe like which is useful as a medicament, and development of a compoundhaving excellent oral absorption and safe CCR4 antagonistic activity isdesired.

The present inventors have made extensive studies to find a compoundhaving CCR4 antagonistic activity, and as a result, have found that theobject is achieved by the compound of the present invention of formula(I), and then have completed the present invention.

Namely, the present invention relates to the followings:

-   1. A compound of formula (I):    wherein ring A, ring B, and ring D each independently represents a    cyclic group which may be substituted;-   J represents a bond or a spacer having 1 to 8 atoms in its main    chain; and-   G represents a bond or a spacer having 1 to 4 atoms in its main    chain; or a salt thereof.-   2. The compound according to the above 1, wherein    wherein D^(J) and D^(G) each independently represents a carbon atom    or a nitrogen atom; and ---- represents a single bond or a double    bond, and    when ---- represents a double bond, D^(J) and D^(G) each represents    a carbon atom.-   3. The compound according to the above 2, wherein ring D is a    carbocyclic ring which may be substituted.-   4. The compound according to the above 2, wherein ring D is a    heterocyclic ring which may be substituted.-   5. The compound according to the above 4, wherein the heterocyclic    ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic    heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms    and/or 1 or 2 sulfur atoms as a hetero atom(s).-   6. The compound according to the above 2, wherein    wherein R^(D) represents a substituent of ring D; and M represents a    3- to 11-membered monocyclic or bicyclic cyclic group which may be    substituted.-   7. The compound according to the above 6, wherein    wherein R^(D) has the same meaning as described in the above 6.-   8. The compound according to the above 1, wherein ring A is a    carbocyclic ring which may be substituted.-   9. The compound according to the above 1, wherein ring A is a    heterocyclic ring which may be substituted.-   10. The compound according to the above 8, wherein the carbocyclic    ring is a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring.-   11. The compound according to the above 9, wherein the heterocyclic    ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic    heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms    and/or 1 or 2 sulfur atoms as a hetero atom(s).-   12. The compound according to the above 10, wherein the carbocyclic    ring is a benzene ring or a naphthalene ring.-   13. The compound according to the above 11 wherein the heterocyclic    ring is a pyridine ring, a pyrazole ring, a dioxaindane ring or a    benzodioxane ring.-   14. The compound according to the above 1, wherein ring B is a    carbocyclic ring which may be substituted.-   15. The compound according to the above 1, wherein ring B is a    heterocyclic ring which may be substituted.-   16. The compound according to the above 14, wherein the carbocyclic    ring is a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring.-   17. The compound according to the above 15, wherein the heterocyclic    ring is a 3- to 15-membered monocyclic, bicyclic or tricyclic    heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms    and/or 1 or 2 sulfur atoms as a hetero atom(s).-   18. The compound according to the above 16, wherein the carbocyclic    ring is a C3-8 monocyclic carbocyclic ring.-   19. The compound according to the above 17, wherein the heterocyclic    ring is a 3- to 8-membered monocyclic heterocyclic ring having 1 to    4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as    a hetero atom(s).-   20. The compound according to the above 18, wherein the carbocyclic    ring is a benzene ring.-   21. The compound according to the above 19, wherein the heterocyclic    ring is a pyridine ring or a thiophene ring.-   22. The compound according to the above 1, wherein J is a spacer    having 1 to 8 atoms in its main chain and containing at least one    oxygen atom,-   23. The compound according to the above 22, wherein the oxygen atom    binds to ring D.-   24. The compound according to the above 22, wherein J is    wherein R³ and R⁴ each independently represents hydrogen or C1-8    alkyl; and E represents a bond or a spacer having 1 to 6 atoms in    its main chain.-   25. The compound according to the above 24, wherein R³ and R⁴ each    independently represents hydrogen or methyl.-   26. The compound according to the above 24, wherein E is a bond,-   27. The compound according to the above 24, wherein E is a spacer    having 1 to 6 atoms in its main chain.-   28. The compound according to the above 27, wherein E is C1-4    alkylene or C1-3 alkyleneoxy.-   29. The compound according to the above 28, wherein E is methylene    or methylenoxy.-   30. The compound according to the above 1, wherein G is a spacer    having 1 to 4 atoms in its main chain and containing at least one    nitrogen atom.-   31. The compound according to the above 30, wherein G is —NR^(T1)—,    —NR^(T1)—SO₂—, —NR^(T1)—CO—, NR^(T1—CO—NR) ^(T1)—,    —NR^(T1)—SO₂—NR^(T1)—, —NR^(T1)—COO—, —NR^(T1)—O—,    —NR^(T1)—NR^(T2)—, —NR^(T1)—W—, —SO₂—NR^(T1)—, —CO—NR^(T1)—,    —OCO—NR^(T1)—, —O—NR^(T1)— or W—NR^(T1)—, wherein W represents a    bivalent C1-3 aliphatic hydrocarbon group which may be substituted;    R^(T1) and R^(T2) each independently represents hydrogen, C1-8 alkyl    which may be substituted, C2-8 alkenyl which may be substituted,    C2-8 alkynyl which may be substituted or a 3- to 8-membered cyclic    group which may be substituted.-   32. The compound according to the above 31, wherein G is —NH—SO₂—.-   33. The compound according to the above 1, wherein the compound is a    compound of formula (A):    wherein R¹ and R² each independently represents (1) hydrogen, (2)    C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) halogen, (6)    cyano, (7) nitro, (8) —CONR⁷R⁸, (9) —COOR⁹, (10) Cyc1 or (11) C1-8    alkyl substituted with 1 to 5 groups selected from (a) —CONR⁷R⁸, (b)    —COOR⁹, (c) —OR¹⁰, (d) —NR¹¹R¹², (e) halogen, and (f) Cyc1; or-   R¹ and R² are taken together to represent C3-4 alkylene,    —CH═CH—CH₂—, —CH₂—CH═CH—, —CH═CH—CH═CH— or —CH═CH—CH₂—CH₂—, wherein    the carbocyclic ring to be formed may be substituted with C1-8    alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, halogen, cyano,    nitro or hydroxyl, wherein R⁷ and R⁸ each independently    represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8    alkynyl, (5) Cyc2, (6) —OR¹³ or (7) C1-8 alkyl, C2-8 alkenyl or C2-8    alkynyl substituted with 1 to 5 groups selected from (a) —OR³, (b)    —NR¹⁴R¹⁵, (c) —NR¹⁶COR¹⁷, (d) halogen, (e) CF₃, and (f) Cyc2; or-   R⁷ and R⁸ are taken together with the adjacent nitrogen atom to    represent a 3- to 8-membered monocyclic heterocyclic ring having at    least one nitrogen atom as a hetero atom(s) and 0 to 3 nitrogen    atoms, 0 to 1 oxygen atom and/or 0 to 1 sulfur atom as an other    hetero atom(s), wherein the heterocyclic ring may be substituted    with (a) C1-8 alkyl, (b) halogen, (c) hydroxyl, or (d) C1-8 alkyl    substituted with hydroxyl;-   R¹³ to R¹⁷ each independently represents (1) hydrogen, (2) C1-8    alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc1, or (6) C1-8    alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc1;-   R⁹ to R¹² each independently represents (1) hydrogen, (2) C1-8    alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc1, or (6) C1-8    alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc1;-   Cyc1 represents a. C3-15 monocyclic, bicyclic- or tricyclic    carbocyclic ring or a 3- to 15-membered monocyclic, bicyclic or    tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2    oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s), wherein    Cyc1 may be substituted with 1 to 5 of R¹⁸;-   R¹⁸ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8    alkynyl, (4) halogen, (5) cyano, (6) nitro, (7) trifluoromethyl, (8)    trifluoromethoxy, (9) —OR¹⁹, (10) —SR²⁰, (11) —NR²¹R²², (12)    —COR²³, (13) —COOR²⁴, (14) —NR²⁵COR²⁶, (15) —CONR²⁷R²⁸, (16) Cyc2,    or (17) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1    to 5 groups selected from (a) halogen, (b) cyano, (c) nitro, (d)    trifluoromethyl, (e) trifluoromethoxy, (f) —OR¹⁹, (g) —SR²⁰, (h)    —NR²¹R²², (i) —COR²³, (j) —COOR²⁴ (k) —NR²⁵COR²⁶, (1) —CONR²⁷R²⁸,    and (m) Cyc2;-   R¹⁹ to R²⁸ each independently represents (1) hydrogen, (2) C1-8    alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc2, or (6) C1-8    alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2; Cyc2    represents a C3-8 monocyclic carbocyclic ring or a 3- to 8-membered    monocyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2    oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s), wherein    Cyc2 may be substituted with 1 to 5 of R²⁹;-   R²⁹ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8    alkynyl, (4) halogen, (5) cyano, (6) nitro, (7) hydroxyl, (8)    trifluoromethyl, (9) trifluoromethoxy, or (10) —OR¹⁰⁰;-   R¹⁰⁰ represents C1-8 alkyl;-   R³ and R⁴ each independently represents hydrogen or C1-8 alkyl;-   E¹ represents a bond or C1-6 alkylene, wherein a carbon atom in the    alkylene group may be substituted with oxygen, sulfur, or —NR³⁰—;-   R³⁰ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8    alkynyl, (4) phenyl, or (5) C1-8 alkyl substituted with phenyl;-   ring A¹ represents a C3-15 monocyclic, bicyclic or tricyclic    carbocyclic ring or a 3- to 15-membered monocyclic, bicyclic or    tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2    oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s);-   R⁵ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8    alkynyl, (4) halogen, (5) cyano, (6) nitro, (7) trifluoromethyl, (8)    trifluoromethoxy, (9) —OR³¹, (10) —NR³²R³³, (11) —NR³⁴COR³⁵, (12)    Cyc3, or (13) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted    with 1 to 5 groups selected from (a) halogen, (b) cyano, (c)    nitro, (d) trifluoromethyl, (e) trifluoromethoxy, (f) —OR³¹, (g)    —NR³²COR³³, (h) —NR³⁴COR³⁵, and (i) Cyc3;-   R³¹ to R³⁵ each independently represents (1) hydrogen, (2) C1-8    alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc3, or (6) C1-8    alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to 5 groups    selected from (a) Cyc3, (b) —OR³⁶ and (c) —NR³⁷R³⁸;-   R³⁶ to R³⁸ each independently represents (1) hydrogen, (2) C1-8    alkyl, (3) —OR³⁹, or (4)—NR⁴⁰R⁴¹;-   R³⁹ to R⁴¹ each independently represents hydrogen or C1-8 alkyl;-   Cyc3 represents a C3-8 monocyclic carbocyclic ring or a 3- to    8-membered monocyclic heterocyclic ring having 1 to 4 nitrogen    atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero    atom(s);-   ring B¹ represents a C3-15 monocyclic, bicyclic or tricyclic    carbocyclic ring or a 3- to 15-membered monocyclic, bicyclic or    tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2    oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s);-   R⁶ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8    alkynyl, (4) halogen, (5) cyano, (6) nitro, (7) trifluoromethyl, (8)    trifluoromethoxy, (9) —OR⁴², (10) —NR⁴³R⁴⁴, (11) —SR¹⁰¹ (12)    —SO₂R¹⁰², (13) —COR¹⁰³, (14) —COOR¹⁰⁴, (15) Cyc2, or (16) C1-8    alkyl, C2-8 alkenyl, or C2-8 alkynyl substituted with 1 to 5 groups    selected from (a) —COOR¹⁰⁴, (b) —NR¹⁰⁵COR¹⁰⁶, and (c) Cyc2;-   R⁴² to R⁴⁴ and R¹⁰¹ to R¹⁰⁶ each independently represents (1)    hydrogen, (2) C1-8 alkyl, (3) Cyc2, or (4) —COR¹⁰⁷, or (5) C1-8    alkyl substituted with 1 to 5 halogen atoms;-   R¹⁰⁷ represents C1-8 alkyl; and-   p and q each independently represents 0 or an integer of 1 to 5.-   34. A prodrug for the compound according to the above 1.-   35. A pharmaceutical composition which comprises the compound of    formula (I):    wherein ring A, ring B, and ring D each independently represents a    cyclic group which may be substituted; J represents a bond or a    spacer having 1 to 8 atoms in its main chain; and G represents a    bond or a spacer having 1 to 4 atoms in its main chain; or a salt    thereof.-   36. The pharmaceutical composition according to the above 35, which    is a chemokine receptor antagonist.-   37. The pharmaceutical composition according to the above 36,    wherein the chemokine receptor is CCR4.-   38. The pharmaceutical composition according to the above 37, which    is a preventive and/or therapeutic agent for CCR4-mediated diseases.-   39. The pharmaceutical composition according to the above 38,    wherein the CCR4-mediated diseases are inflammatory and/or allergic    diseases, metabolism and/or endocrine system diseases, cancer    diseases or infections.-   40. The pharmaceutical composition according to the above 39,    wherein the CCR4-mediated diseases are inflammatory and/or allergic    diseases.-   41. The pharmaceutical composition according to the above 40,    wherein the inflammatory and/or allergic diseases are respiratory    diseases or dermatosis.-   42. The pharmaceutical composition according to the above 41,    wherein the respiratory diseases are asthma.-   43. The pharmaceutical composition according to the above 41,    wherein the dermatosis is atopic dermatitis.-   44. A method for preventing and/or treating CCR4-mediated diseases    in a mammal, which comprises administering to a mammal an effective    amount of the compound according to the above 1 or a salt thereof.-   45. Use of the compound according to the above 1 or a salt thereof    for the manufacture of a preventive and/or therapeutic agent for    CCR4-mediated diseases.-   46. A pharmaceutical composition which comprises: a preventive    and/or therapeutic agent for CCR4-mediated diseases, which comprises    the compound according to the above 1 or a salt thereof as an active    ingredient; and one or at least two medicaments selected from a    bronchodilator drug, a steroid drug, a non-steroidal    antiinflammatory drug, a leukotriene receptor antagonist, a    phosphodiesterase inhibitor, an immunosuppressant, an anti-allergic    drug, a mediator-release inhibitor, an antihistamine drug, a    metabolism promoter and/or a chemokine inhibitor.-   47. The pharmaceutical composition according to the above 35, which    is an inhibitor of effector cell function.-   48. The pharmaceutical composition according to the above 47, which    is an inhibitor of cell migration function.-   49. The pharmaceutical composition according to the above 35, which    is a TNFα regulator.

In the present specification, the “cyclic group” in the “cyclic groupwhich may be substituted” represented by ring A, ring B and ring Dincludes, for example, a carbocyclic ring, a heterocyclic ring and thelike.

The carbocyclic ring includes, for example, a “C3-15 monocyclic,bicyclic or tricyclic carbocyclic ring”, and the like. The “C3-15monocyclic, bicyclic or tricyclic carbocyclic ring” includes a C3-15monocyclic, bicyclic or tricyclic unsaturated carbocyclic ring, orpartially or completely saturated one thereof, a spiro-bound bicycliccarbocyclic ring and a crosslinked bicyclic carbocyclic ring.

The “C3-15 monocyclic, bicyclic or tricyclic unsaturated carbocyclicring, or partially or completely saturated one thereof” includes, forexample, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane,cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene,perhydropentalene, azulene, perhydroazulene, indene, perhydroindene,indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene, heptalene, perhydroheptalene, biphenylene,as-indacene, s-indeacene, acenaphthylene, acenaphthene, fluorene,phenalene, phenanthrene, anthracene rings, and the like. The“spiro-bound bicyclic carbocyclic ring” includes, for example,spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane rings, and thelike. The “crosslinked bicyclic carbocyclic ring” includes, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.1]hepta-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hepta-2-ene, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane,bicyclo[2.2.2]octa-2-ene, adamantane, noradamantane rings, and the like.Among these, a “C3-15 monocyclic, bicyclic or tricyclic aromaticcarbocyclic ring” includes, for example, benzene, azulene, naphthalene,phenanthrene, anthracene rings, and the like.

The heterocyclic ring includes, for example, a “3- to 15-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, and the like. Herein, the “3- to 15-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)” includes 3- to 15-membered monocyclic, bicyclic ortricyclic unsaturated heterocyclic ring having 1 to 4 nitrogen atoms, 1or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s), orpartially or completely-saturated one thereof, a spiro-bound bicyclicheterocyclic ring and a crosslinked bicyclic heterocyclic ring.

The “3- to 15-membered monocyclic, bicyclic or tricyclic unsaturatedheterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s), or partially orcompletely saturated one thereof” includes, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine,tetrahydroxepine, perhydroxepine, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydroxazole,tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine,tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine,perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine,perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindane, benzodioxane, chroman,benzodithiolane, benzodithiane, 6,7-dihydro-5H-cyclopenta[b]pyrazine,5H-cyclopenta[b]pyrazine, imidazo[2,1-b][1,3]thiazole rings, and thelike. The “spiro-bound bicyclic heterocyclic ring” includes, forexample, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane,dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane,dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane,azaspiro[5.5]undecane, oxaspiro[5.5]undecane, dioxaspiro[5.5]undecanerings, and the like. The “crosslinked bicyclic heterocyclic ring”includes, for example, azabicyclo[2.2.1]heptane,oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[3.2.1]octane, oxabicyclo[3.2. I]octane,azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane rings, and the like.

Among these, the “3- to 15-membered monocyclic, bicyclic or tricyclicaromatic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s)” includes, forexample, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole, indole,isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,indazole, quinoline, isoquinoline, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, dibenzothiophene, phenanthridine, phenanthroline,perimidine rings, and the like.

In the present specification, the “substituent” in the “cyclic groupwhich may be substituted” represented by ring A and ring B is notparticularly limited, so long as it is a substituent. The “substituent”includes, for example, substituents as exemplified below.

The “substituent” in the above-described “cyclic group which may besubstituted” includes, for example, (1) a substituent selected from thefollowing Group I, (2) a substituent selected from the following GroupII, (3) 3- to 15-membered cyclic group which may be substituted, (4)carbamoyl which may be substituted, (5) an aliphatic hydrocarbon groupwhich may be substituted, and the like. The substituents may besubstituted in the number of 1 to 10, preferably 1 to 5, more preferably1 to 3, at a substitutable position.

<Group I>

-   -   (1) halogen (chlorine, bromine, fluorine, and iodine), (2)        cyano, (3) nitro, (4) trifluoromethyl, (5) trifluoromethoxy, (6)        oxo and (7) thioxo.        <Group II>    -   (1) —OR^(a1), (2) —NR^(a1)R^(a2), (3) —NR^(a1)COR^(a2), (4)        —COR^(a1), (5) —SR^(a1), (6) —SOR^(a1), (7) —SO₂R^(a1) and (8)        —COR^(a1),        wherein R^(a1) and R^(a2) each independently represents (a)        hydrogen, (b) an aliphatic hydrocarbon group which may be        substituted, or (c) a 3- or 15-membered cyclic group which may        be substituted. If plural substituents are selected, plural        R^(a1) or plural R^(a2) are the same or different.

Herein, the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbongroup which may be substituted” represented by R^(a1) and R^(a2)includes, for example, a “straight or branched aliphatic hydrocarbongroup”, and the like. The “straight or branched aliphatic hydrocarbongroup” includes, for example, a “C1-8 aliphatic hydrocarbon group”, andthe like.

The “C1-8 aliphatic hydrocarbon group” includes, for example, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, and the like.

The C1-8 alkyl includes, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, isomersthereof, and the like.

The C2-8 alkenyl includes, for example, vinyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl,hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl,octatrienyl, isomers thereof, and the like.

The C2-8 alkynyl includes, for example, ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl,hexadiynyl, heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl,octatriynyl, isomers thereof, and the like.

The “substitutent” in the “aliphatic hydrocarbon group which may besubstituted” represented by R^(a1) and R^(a2) includes, for example, (1)a substituent selected from the above-described Group I, (2) asubstituent selected from the following Group III, (3) a 3- to15-membered cyclic group which may be substituted, and the like. Thesubstituents may be substituted in the number of 1 to 8, preferably 1 to5, at a substitutable position.

<Group III>

-   -   (1) —OR^(b1) and (2) —NR^(b1)R^(b2),        wherein R^(b1) and R^(b2) each independently represents (a)        hydrogen, (b) hydroxyl, (c) cyano, (d) C1-8 alkyl (which has the        same meaning as described in the above), (e) C1-8 alkoxy (e.g.,        methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,        heptyloxy, octyloxy, isomers thereof, etc.), (f) monosubstituted        or disubstituted C1-8 alkylamino (e.g., methylamino, ethylamino,        propylamino, dimethylamino, diethylamino, etc.), (g) C1-8 alkyl        substituted with the “monosubstituted or disubstituted C1-8        alkylamino” (the C1-8 alkyl has the same meaning as described in        the above), and (h) C1-8 alkoxy substituted with the        “monosubstituted or disubstituted C1-8 alkylamino” (the C1-8        alkoxy has the same meaning as described in the above). If        plural substituents are selected, plural R^(b1) or plural R^(b2)        are the same or different.

In the present specification, the “3- or 15-membered cyclic group” inthe “3- or 15-membered cyclic group which may be substituted” includes,for example, the above-described “C3-15 monocyclic, bicyclic ortricyclic carbocyclic ring”, the above-described “3- to 15-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, and the like.

The “substituent” in the “3- or 15-membered cyclic group which may besubstituted” includes, for example, (1) a substituent selected from theabove-described Group I, (2) an aliphatic hydrocarbon group which may besubstituted, (3) a substituent selected from the following Group IV, (4)a 3- to 8-membered cyclic group which may be substituted, and the like.The substituents may be substituted in the number of 1 to 10, preferably1 to 5, more preferably 1 to 3, at a substitutable position. The“aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group whichmay be substituted” as used herein includes, for example, theabove-described “C1-8 aliphatic hydrocarbon group”, and the like. The“substitutent” in the “aliphatic hydrocarbon group which may besubstituted” includes, for example, (1) a substituent selected from theabove-described Group I, (2) a substituent selected from the followingGroup IV, (3) 3- to 8-membered cyclic group which may be substituted,and the like. The substituents may be substituted in the number of 1 to8, preferably 1 to 5, at a substitutable position.

<Group IV>

-   -   (1) —OR^(c1), (2) —SR^(c1), (3) —NR^(c1)R^(c2), (4)        —COR^(c1), (5) —COOR^(c1), (6) —NR^(c1)COR^(c2), (7)        —CONR^(c1)R^(c2), (8) —SOR^(c1) and (9) a —SO₂R^(c1),        wherein R^(c1) and R^(c2) each independently represents (a)        hydrogen, (b) a 3- to 8-membered cyclic group which may be        substituted, or (c) an aliphatic hydrocarbon group which may be        substituted with a 3- to 8-membered cyclic group which may be        substituted. If plural substituents are selected, plural R^(c1)        or plural R^(c2) are the same or different.

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich may be substituted with a 3- to 8-membered cyclic group which maybe substituted” represented by R^(c1) or R^(c2) as used herein includes,for example, the above-described “C1-8 aliphatic hydrocarbon group”, andthe like.

In the present specification, “3- to 8-membered cyclic group” in the “3-to 8-membered cyclic group which may be substituted” includes, forexample, a “C3-8 monocyclic carbocyclic ring”, a “3- to 8-memberedmonocyclic heterocyclic ring”, and the like. The “C3-8 monocycliccarbocyclic ring” as used herein include a C3-8 monocyclic unsaturatedcarbocyclic ring, or partially or completely saturated one thereof.

The “C3-8 monocyclic unsaturated carbocyclic ring, or partially orcompletely saturated one thereof” includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene rings, and thelike. Among these, “C3-8 monocyclic aromatic carbocyclic ring” includes,for example, a benzene ring, and the like.

The “3- to 8-membered monocyclic heterocyclic ring” includes, forexample, a “3- to 8-membered monocyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, and the like. The “3- to 8-membered monocyclicheterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s)” as used herein includes,for example, a 3- to 8-membered monocyclic unsaturated heterocyclic ringhaving 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfuratoms as a hetero atom(s), or partially or completely saturated onethereof.

The “3- to 8-membered monocyclic unsaturated heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s), or partially or completely saturated one thereof”includes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine,oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine,tetrahydroxepine, perhydroxepine, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydroxazole,tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine,tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine,perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine,perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithianerings, and the like. Among these, the “3- to 8-membered monocyclicaromatic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s)” includes, forexample, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole rings, and thelike.

The “substituent” in the “3- to 8-membered cyclic group which may besubstituted” includes, for example, (1) a substituent selected from theabove-described Group I, (2) C1-8 alkyl (which has the same meaning asdescribed in the above), (3) C2-8 alkenyl (which has the same meaning asdescribed in the above), (4) C2-8 alkynyl (which has the same meaning asdescribed in the above), (5) hydroxyl, and the like. The substituentsmay be substituted in the number of 1 to 8, preferably 1 to 5, at asubstitutable position.

The “carbamoyl which may be substituted” as the “substituent” in the“cyclic group which may be substituted” represented by ring A and ring Bincludes, for example, N-monosubstituted carbamoyl and N,N-disubstitutedcarbamoyl, in addition to unsubstituted carbamoyl. The“N-monosubstituted carbamoyl” means carbamoyl having one substituent onthe nitrogen atom, and the “N,N-disubstituted carbamoyl” means carbamoylhaving two substituents on the nitrogen atom. The substituent of thecarbamoyl includes, for example, (1) the above-described “3- to15-membered cyclic group which may be substituted”, (2) an aliphatichydrocarbon group which may be substituted, (3) an optionally protectedhydroxyl, and the like. These substituents may be substituted in thenumber of 1 to 2 at a substitutable position. The substituent of thecarbamoyl in the “N,N-disubstituted carbamoyl”, together with thenitrogen atom to which they are bound, form (4) 3- to 8-memberednitrogen-containing heterocyclic ring which may be substituted.

The “optionally protected hydroxyl” as used herein includes, forexample, protected hydroxyl, in addition to hydroxyl. The “protectivegroup” in the “protected hydroxyl” includes, for example, (1) C1-8 alkylwhich may be substituted (wherein the C1-8 alkyl has the same meaning asdescribed in the above), (2) C2-8 alkenyl which may be substituted(wherein the C2-8 alkenyl has the same meaning as described in theabove), (3) C2-8 alkynyl which may be substituted (wherein the C2-8alkynyl has the same meaning as described in the above), (4) theabove-described “3- to 15-membered cyclic group which may besubstituted”, and the like. The “substituent” in the “C1-8 alkyl whichmay be substituted”, the “C2-8 alkenyl which may be substituted”, andthe “C2-8 alkynyl which may be substituted” as used herein includes, forexample (1) the above-described “3- to 15-membered cyclic group whichmay be substituted”, (2) a substituent selected from the above-describedGroup I, and the like. The substituents may be substituted in the numberof 1 to 8, preferably 1 to 5, at a substitutable position.

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich may be substituted” as the substituent of the “N-monosubstitutedcarbamoyl” and the “N,N-disubstituted carbamoyl” includes, for example,the above-described “C1-8 aliphatic hydrocarbon group”, and the like.The “substituent” in the “aliphatic hydrocarbon group which may besubstituted” as used herein includes, for example, (1) a substituentselected from the above-described Group I, (2) the above-described “3-to 15-membered cyclic group which may be substituted”, (3) a substituentselected from the above-described Group II, and the like. Thesubstituents may be substituted in the number of 1 to 8, preferably 1 to5, at a substitutable position.

In the present specification, the “3- to 8-membered nitrogen-containingheterocyclic ring” in the “3- to 8-membered nitrogen-containingheterocyclic ring which may be substituted” includes, for example, the“3- to 8-membered monocyclic heterocyclic ring having at least onenitrogen atom as a hetero atom(s) and 0 to 3 nitrogen atoms, 0 to 1oxygen atom and/or 0 to 1 sulfur atom as an other hetero atom(s)”, andthe like. The “3- to 8-membered monocyclic heterocyclic ring having atleast one nitrogen atom as a hetero atom(s) and 0 to 3 nitrogen atoms, 0to 1 oxygen atom and/or 0 to 1 sulfur atom as an other hetero atom(s)”as used herein includes, for example 3- to 8-membered monocyclicunsaturated heterocyclic ring having at least one nitrogen atom as ahetero atom(s) and 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and/or 0 to1 sulfur atom as an other hetero atom(s), or partially or completelysaturated one thereof. The “3- to 8-membered monocyclic unsaturatedheterocyclic ring having at least one nitrogen atom as a hetero atom(s)and 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and/or 0 to 1 sulfur atomas an other hetero atom(s), or partially or completely saturated onethereof” includes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydroxazole, tetrahydroxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine,tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine,perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine,perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine rings, and the like. Among these, the “3- to 8-memberedmonocyclic aromatic heterocyclic ring having at least one nitrogen atomas a hetero atom(s) and 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and/or0 to 1 sulfur atom as an other hetero atom(s)”includes, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, thiadiazole rings, and the like.

The “substituent” in the “3- to 8-membered nitrogen-containingheterocyclic ring which may be substituted” includes, for example, (1) asubstituent selected from the above-described Group I, (2) hydroxyl, (3)C1-8 alkyl (wherein the C1-8 alkyl has the same meaning as described inthe above) which may be substituted with 1 to 8 hydroxyl groups, and thelike. The substituents may be substituted in the number of 1 to 8,preferably 1 to 5, at a substitutable position.

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich may be substituted” as the “substituent” in the “cyclic groupwhich may be substituted” represented by ring A and ring B includes, forexample, the above-described “C1-8 aliphatic hydrocarbon group”, and thelike. The “substituent” in the “aliphatic hydrocarbon group which may besubstituted” as used herein includes, for example, (1) a substituentselected from the above-described Group I, (2) the above-described “3-to 15-membered cyclic group which may be substituted”, (3) theabove-described “carbamoyl which may be substituted”, (4) a substituentselected from the above-described Group II, and the like. Thesubstituents may be substituted in the number of 1 to 8, preferably 1 to5, at a substitutable position.

The “substituent” in the “cyclic group which may be substituted”represented by ring D is not particularly limited, so long as it is asubstituent. The substituent includes, for example, the substituentsrepresented by ring RD, and the like.

The “substituent of ring D” represented by ring RD includes, forexample, the above-described substituents exemplified as the“substituent” in “cyclic ring which may be substituted” represented by Aand B, and the like. The substituents may be substituted in the numberof 1 to 10, preferably 1 to 5, more preferably 1 to 3, at asubstitutable position.

The “spacer having 1 to 4 atoms in its main chain” represented by Gmeans a space in which 1 to 4 atoms exist successively in its mainchain. The “atomic number in its main chain” is counted such that theatoms of the main chain are minimized. For example, the atomic number in1,2-cyclopentylene is counted as 2, and in 1,3-cyclopentylene as 3.

The “spacer having 1 to 4 atoms in its main chain” includes, forexample, a bivalent group having 1 to 4 successive atoms in its mainchain and consisting of 1 to 4 groups selected from —O—, —S—, —CO—,—SO—, —SO₂—, a nitrogen atom which may be substituted, a bivalent C1-4aliphatic hydrocarbon group which may be substituted, a bivalent C3-8monocyclic carbocyclic group which may be substituted, and a bivalent 3-to 8-membered monocyclic heterocyclic group which may be substituted,and the like. The “nitrogen atom which may be substituted” as usedherein represents —NH—, and further a group in which the hydrogen atomin the “—NH—” is substituted with (1) C1-8 alkyl which may besubstituted (the C1-8 alkyl has the same meaning as described in theabove), (2) C2-8 alkenyl which may be substituted (the C2-8 alkenyl hasthe same meaning as described in the above), (3) C2-8 alkynyl which maybe substituted (the C2-8 alkynyl has the same meaning as described inthe above), (4) the above-described “3- to 8-membered cyclic group whichmay be substituted”, or the like. The “substituent” in the “C1-8 alkylwhich may be substituted”, the “C2-8 alkenyl which may be substituted”and the “C2-8 alkynyl which may be substituted” as the “substitutent” ofthe “nitrogen which may be substituted” as use herein includes, forexample, (a) hydroxyl, (b) the above-described “3- to 8-membered cyclicring which may be substituted”, and the like. The substituents may besubstituted in the number of 1 to 8, preferably 1 to 5, at asubstitutable position.

The “bivalent C1-4 aliphatic hydrocarbon group” in the “bivalent C1-4aliphatic hydrocarbon group which may be substituted” includes, forexample, C1-4 alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,etc.), C2-4 alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—,—(CH₂)₂—CH═CH—, —CH═CH—(CH₂)₂—, —CH₂—CH═CH—CH₂—, etc.), C2-4 alkynylene(e.g., —C—C—, —CH₂—C≡C—, —C≡C—CH₂—, —(CH₂)₂—C≡C—, —C≡C—(CH₂)₂—,—CH₂—C≡C—CH₂—, etc.), and the like. The “substituent” in the “a bivalentC1-4 aliphatic hydrocarbon group which may be substituted” includes, forexample, (1) C1-8 alkyl (which has the same meaning as described in theabove), (2) C1-8 alkoxy (which has the same meaning as described in theabove), (3) halogen (which has the same meaning as described in theabove), (4) hydroxyl, (5) oxo, (6) thioxo, (7) cyano, (8)═N—OR^(n),wherein R^(n) represents hydrogen or has the same meaning as the“substituent” in the “nitrogen which may be substituted”, and the like.The substituents may be substituted in the number of 1 to 5, preferably1 to 2, at a substitutable position.

In addition, the “bivalent C3-8 monocyclic carbocyclic group” in the“bivalent C3-8 monocyclic carbocyclic group which may be substituted”includes, for example, a bivalent group made by removing any twohydrogen atoms from the rings exemplified as the “C3-8 monocycliccarbocyclic ring”, and the like. The “substituent” in the “bivalent C3-8monocyclic carbocyclic ring which may be substituted” includes, forexample, those exemplified as the “substituent” in the above-described“3- to 8-membered cyclic group which may be substituted”, and the like.The substituents may be substituted in the number of 1 to 8, preferably1 to 5, at a substitutable position.

The “bivalent 3- to 8-membered monocyclic heterocyclic group” in the“bivalent 3- to 8-membered monocyclic heterocyclic group which may besubstituted” includes, for example, a bivalent group made by removingany two hydrogen atoms from the rings exemplified as the above-described“3- to 8-membered monocyclic heterocyclic ring”, and the like. The“substituent” in the “bivalent 3- to 8-membered monocyclic heterocyclicgroup which may be substituted” includes, for example, those exemplifiedas the substituent in the above-described “3- to 8-membered cyclic groupwhich may be substituted”, and the like. The substituents may besubstituted in the number of 1 to 8, preferably 1 to 5, at asubstitutable position.

The “spacer having 1 to 4 atoms in its main chain and containing atleast one nitrogen atom” represents a bivalent group containing at leastone the above-described “nitrogen atom which may be substituted” amongthe groups, in the “spacer having 1 to 4 atoms in its main chain”. Ifthe “nitrogen atom which may be substituted” is contained in two ormore, the subsitutents of each nitrogen atom are the same or different.The “spacer having 1 to 4 atoms in its main chain and containing atleast one nitrogen atom” preferably includes, for example, —NR^(T1)—,—NR^(T1)—SO₂—, —NR^(T1)—CO—, —NR^(T1)—CO—NR^(T2)—, —NR^(T1—SO)₂—NR^(T2)—, —NR^(T1)—COO—, —NR^(T1)—O—, —NR^(T1)—NR^(T2)—, —NR^(T1)—W—,—SO₂—NR^(T1)—, —CO—NR^(T1)—, —OCO—NR^(T1)—, —O—NR^(T1)—, —W—NR^(T1)—,wherein W represents the “bivalent C1-3 aliphatic hydrocarbon groupwhich may be substituted”, and R^(T1) and R^(T2) each independentlyrepresents hydrogen or has the same meaning as the substituents in theabove-described “nitrogen atom which may be substituted”, and the like.The “bivalent C1-3 aliphatic hydrocarbon group” in the “bivalent C1-3aliphatic hydrocarbon group which may be substituted” represented by Was used herein represents C1-3 alkylene (e.g., —CH₂—, —(CH₂)₂—,—(CH₂)₃—, etc.), C2-3 alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—,—CH═CH—CH₂—, etc.) and C2-3 alkynylene (e.g., —C≡C—, —CH₂—C≡C—,—C≡C—CH₂—, etc.), among the groups exemplified as the above-described“bivalent C1-4 aliphatic hydrocarbon group which may be substituted”.Furthermore, the “substituent” in the “bivalent C1-3 aliphatichydrocarbon group which may be substituted” has the same meaning as thesubstituent in the above-described “bivalent C1-4 aliphatic hydrocarbongroup which may be substituted”.

The “spacer having 1 to 8 atoms in its main chain” represented by Jmeans a spacer in which 1 to 8 atoms exist successively in its mainchain. The “atomic number in its main chain” as used herein is countedsuch that the atoms of the main chain are minimized as in the “spacerhaving 1 to 4 atoms in its main chain”. For example, the atomic numberin 1,4-phenylene is counted as 4, and in 1,3-phenylene as 3.

The “spacer having 1 to 8 atoms in its main chain” includes, forexample, a bivalent group having 1 to 8 successive atoms in its mainchain and containing 1 to 8 groups selected from —O—, —S—, —CO—, —SO—,—SO₂—, the above-described “nitrogen atom which may be substituted”, abivalent C1-8 aliphatic hydrocarbon group which may be substituted, theabove-described “bivalent C3-8 monocyclic carbocyclic group which may besubstituted”, and the above-described “bivalent 3- to 8-memberedmonocyclic heterocyclic group which may be substituted”, and the like.

The “bivalent C1-8 aliphatic hydrocarbon group” in the “bivalent C1-8aliphatic hydrocarbon group which may be substituted” includes, forexample, C1-8 alkylene (e.g., methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,octamethylene, etc.), C2-8 alkenylene (e.g., ethenylene, propenylene,butenylene, butadiene, pentenylene, pentadienylene, hexenylene,hexadienylene, heptenylene, heptadienylene, octenylene, octadienylene,etc.), C2-8 alkynylene (e.g., ethynylene, propynylene, butynylene,butadiynylene, pentynylene, pentadiynylene, hexynylene, hexadiynylene,heptynylene, heptadiynylene, octynylene, octadiynylene, etc.), and thelike. The “substituent” in the “bivalent C1-8 aliphatic hydrocarbongroup which may be substituted” includes, for example, those exemplifiedas the “substituent” in the above-described “bivalent C1-4 aliphatichydrocarbon group which may be substituted”, and the like. Thesubstituents may be substituted in the number of 1 to 10, preferably 1to 5, more preferably 1 to 3, at a substitutable position.

The “spacer having 1 to 8 atoms in its main chain and containing atleast one oxygen atom” represents a bivalent group containing at leastone —O— among the groups in the above-described “spacer having 1 to 8atoms in its main chain”. The “spacer having 1 to 8 atoms in its mainchain and containing at least one oxygen atom” is preferably those inwhich an oxygen atom is bound to ring D.

The “spacer having 1 to 6 atoms in its main chain” represented by Eincludes those in which 1 to 6 atoms exist successively in its mainchain among the above-described “spacer having 1 to 8 atoms in its mainchain”. The “spacer having 1 to 6 atoms in its main chain” representedby E is preferably, for example, the “C1-6 alkylene which may besubstituted”, the “C1-5 alkyleneoxy which may be substituted”, and thelike. The “substituent” in the “C1-6 alkylene which may be substituted”and the “C1-5 alkyleneoxy which may be substituted” as used hereinincludes, for example, those exemplified as the “substituent” in theabove-described “bivalent C1-4 aliphatic hydrocarbon group which may besubstituted”, and the like. The substituents may be substituted in thenumber of 1 to 8, preferably 1 to 5, more preferably 1 to 3, at asubstitutable position.

The C1-6 alkylene includes, for example, methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene, isomersthereof, and the like.

The C1-5 alkyleneoxy includes, for example, methylenoxy, ethyleneoxy,trimethylenoxy, tetramethylenoxy, pentamethylenoxy, isomers thereof, andthe like.

The C1-4 alkylene includes, for example, methylene, ethylene,trimethylene, tetramethylene, isomers thereof, and the like.

The C1-3 alkyleneoxy includes, for example, methylenoxy, ethyleneoxy,trimethylenoxy, isomers thereof, and the like.

The “3- to 11-membered monocyclic or bicyclic cyclic group” in the “3-to 11-membered monocyclic or bicyclic cyclic group which may besubstituted” represented by M includes, for example, a “3- to11-membered monocyclic or bicyclic carbocyclic ring”, a “3- to11-membered monocyclic or bicyclic heterocyclic ring containing 1 or 2nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, and the like. The “3- to 11-membered monocyclic orbicyclic carbocyclic ring” as used herein includes a C3-11 monocyclic orbicyclic unsaturated carbocyclic ring, or partially or completelysaturated one thereof, a spiro-bound bicyclic carbocyclic ring and acrosslinked bicyclic carbocyclic ring. The “C3-11 monocyclic or bicyclicunsaturated carbocyclic ring, or partially or completely saturated onethereof” includes, for example, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cycloundecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene rings, and the like. The“spiro-bound bicyclic carbocyclic ring” includes, for example,spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane rings, and thelike. The “crosslinked bicyclic carbocyclic ring” includes, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.1]hepta-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hepta-2-ene, bicyclo[2.2.2]octane,bicyclo[2.2.2]octa-2-ene, adamantane, noradamantane rings, and the like.Among these, a “C3-11 monocyclic or bicyclic aromatic carbocyclic ring”includes, for example, benzene, azulene, naphthalene rings, and thelike.

The “3- to 11-membered monocyclic or bicyclic heterocyclic ringcontaining 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2sulfur atoms as a hetero atom(s)” includes a 3- to 11-memberedmonocyclic or bicyclic unsaturated heterocyclic ring containing 1 or 2nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s), or partially or completely saturated one thereof, aspiro-bound bicyclic heterocyclic ring and a crosslinked bicyclicheterocyclic ring. The “3- to 11-membered monocyclic or bicyclicunsaturated heterocyclic ring containing 1 or 2 nitrogen atoms, 1 or 2oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s), orpartially or completely saturated one thereof” includes, for example,pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene,thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,oxazine, oxazepine, oxadiazepine, thiazine, thiazepine, thiadiazepine,indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,benzimidazole, chromene, benzoxepine, benzoxazepine, benzoxadiazepine,benzothiepine, benzothiazepine, benzothiadiazepine, benzoazepine,benzodiazepine, benzofurazan, benzothiadiazole, aziridine, azetidine,pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine,tetrahydroxepine, perhydroxepine, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydroxazole,tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydroxazine, tetrahydroxazine,dihydroxazepine, tetrahydroxazepine, perhydroxazepine,dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine,dihydrothiazine, tetrahydrothiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine,dioxolane, dioxane, dithiolane, dithiane, dioxaindane, benzodioxane,chroman, benzodithiolane, benzodithiane rings, and the like. The“spiro-bound bicyclic heterocyclic ring” includes, for example,azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane,azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane,dioxaspiro[4.5]decane, oxazaspiro[4.5]decane, azaspiro[5.5]undecane,oxaspiro[5.5]undecane, dioxaspiro[5.5]undecane rings, and the like. The“crosslinked bicyclic heterocyclic ring” includes, for example,azabicyclo[2.2.]heptane, oxabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,oxabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane,diazabicyclo[2.2.2]octane rings, and the like. Among these, the “3- to1-membered monocyclic or bicyclic aromatic heterocyclic ring containing1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms asa hetero atom(s)” includes, for example, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole,isoxazole, thiazole, isothiazole, furazan, indole, isoindole,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,benzofurazan, benzothiadiazole rings, and the like.

The “substituent” in the “3- to 11-membered monocyclic or bicycliccyclic group which may be substituted” represented by M as used hereinincludes, for example, the above-described substituents represented byR^(D). The substituents may be substituted in the number of 1 to 10,preferably 1 to 5, more preferably 1 to 3, at a substitutable position.

In formula (A), the “3- to 8-membered monocyclic heterocyclic ringhaving at least one nitrogen atom as a hetero atom(s) and 0 to 3nitrogen atoms, 0 to 1 oxygen atom and/or 0 to 1 sulfur atom as an otherhetero atom(s)” includes, for example a 3- to 8-membered monocyclicheterocyclic aryl having at least one nitrogen atom as a hetero atom(s)and 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and/or 0 to 1 sulfur atomas an other hetero atom(s), or partially or completely saturated onethereof. Examples include pyrrole, imidazole, triazole, tetrazole,pyrazole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydroxazole, tetrahydroxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine,tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine,perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine,perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine rings, and the like.

In formula (A), the “C3-15 monocyclic, bicyclic or tricyclic carbocyclicring” includes a C3-15 monocyclic, bicyclic or tricyclic carbocyclicaryl, or partially or completely one thereof. Examples includescyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane,cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene,acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene,anthracene rings, and the like.

In formula (A), the “3- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s)” includes a 3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic arylcontaining hetero atoms selected 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s), or partially orcompletely saturated one thereof.

The 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclicaryl having 1 to 4 nitrogen atoms, 1 or 2-oxygen atoms and/or 1 or 2sulfur atoms as a hetero atom(s)-includes, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidinerings, and the like. The partially or completely saturated 3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic aryl having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s) includes, for example, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine,tetrahydroxepine, perhydroxepine, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydroxazole,tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole(oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine,tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine,perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine,perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrodibenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindane, benzodioxane, chroman, benzodithiolane, benzodithianerings, and the like.

In formula (A), the C3-8 monocyclic carbocyclic ring includes C3-8monocyclic carbocyclic aryl, or partially or completely saturated onethereof. Examples include cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene,cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene rings, and the like.

In formula (A), the 3- to 8-membered monocyclic heterocyclic ring having1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms asa hetero atom(s) includes, for example, the 3- to 8-membered monocyclicheterocyclic aryl having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s) or partially orcompletely saturated one thereof. The 3- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic aryl having 1 to 4 nitrogen atoms, 1or 2 oxygen atoms and/or 12 sulfur atoms as a hetero atom(s) includes,for example, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan,pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine rings, and the like. Furthermore, the partially orcompletely saturated 3- to 8-membered monocyclic heterocyclic arylhaving 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfuratoms as a hetero atom(s) includes, for example, aziridine, azetidine,pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane,oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepin, perhydrothiepin,dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole,tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole(thiazolidine), dihydroisothiazole, tetrahydroisothiazole(isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole,tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine,dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine,tetrahydroxazepine, perhydroxazepine, dihydroxadiazepine,tetrahydroxadiazepine, perhydroxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane,dithiane rings, and the like.

The C3-4 alkylene includes, for example, trimethylene, tetramethyleneand isomers thereof.

In the present specification, the effector cells include all T cellsexcept naive T cells. The naive T cells mean T cells which receive noantigen stimulation. The effector cells include, for example, RAnegative and/or RO positive T cells. The “RA negative and/or RO positiveT cells” include, for example, Th1 cells, Th2 cells, cytotoxicT-lymphocytes (CTL), central memory T cells (TCM), effector memory Tcell (TEM), and the like. RA and RO mean cell surface antigens. The term“negative” means that surface antigen can not be detected, and the term“positive” means that surface antigen can be detected. A method used todetect the surface antigen includes all the methods of detecting asurface antigen known so far. For example, it includes techniques usedfor the skilled persons in the art to detect proteins (e.g., flowcytometry (FACS), immunostaining, Western blot, fluorescent antibodymethod, etc.) or equivalent techniques thereof. TCM and TEM are thosedefined in literatures (Nature. 1999 Oct. 14; 401 (6754): 708-12.). Inthe present invention, effector cells are preferably effects cells whichexpress CCR4, i.e., CCR4 positive effector cells.

In the present specification, effector cell functions include all theeffector cell functions related to CCR4. The effector cell functionsrelated to CCR4 include, for example, cell migration, permeationincrease to blood vessel wall, tissue infiltration, tissue accumulation,release of humoral factor, expression of cell surface antigen.

In the present specification, TNFα regulating activity mean activity ofregulating TNFα amount in the living body, preferably reducing TNFαamount in the tissue or the blood, more specifically, reducing TNFαamount in the tissue or the blood in various diseases known to increaseTNFα amount in the tissue or the blood.

Unless otherwise specified, the present invention includes all isomers.For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene,alkenylene, alkynylene, etc. include straight or branched ones. Inaddition, the present invention also include isomers on double bond,ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atoms (R-, S-isomer, α-, β-configuration, enantiomer,diastereomer), optically active isomers (D-, L-, d-, l-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, rotational isomers,mixtures thereof at any ratios and racemic mixtures.

Salts

Salts of the compound of formula (I) include all non-toxic salts andpharmacologically acceptable salts. The pharmacologically acceptablesalts are preferably non-toxic and water-soluble salts. Suitable saltsof the compound of formula (I) include, for example, salts of alkalimetals (potassium or sodium, lithium, etc.), salts of alkaline earthmetals (calcium or magnesium, etc.), ammonium salts (tetramethylammoniumsalts, tetrabutylammonium salts, etc.), salts with organic amines(triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine orN-methyl-D-glucamine, etc.) and acid addition salts [salts of inorganicacids (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,nitrate, etc.), salts of organic acids (acetate, trifluoroacetate,lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,isethionate, glucuronate, gluconate, etc.), and the like]. Salts of thecompound of the present invention also include solvates, or solvates ofthe above-described alkali (alkaline earth) metal salts, ammonium salts;organic amine salts, and acid addition salts of the compound of thepresent invention, and the like. The solvates are preferably non-toxicand water-soluble. The appropriate solvates include, for example,solvates such as water, alcohol solvents (ethanol, etc.), and the like.The compound of the present invention may be converted into non-toxicand pharmaceutically acceptable salts by a known method.

Furthermore, the salts also include quaternary ammonium salts. Thequaternary ammonium salts of the compound of formula (I) mean compoundswhere a nitrogen atom of the compound of formula (I) is quaternized byR⁰ (R⁰ represents C1-8 alkyl or C1-8 alkyl substituted with phenyl).

Furthermore, the salts also include N-oxides. The compound of thepresent invention can be converted to N-oxide by any known method.N-oxides are the compounds where nitrogen of the compound of formula (I)is oxidized.

The prodrug for the compound of formula (I) means a compound which isconverted to the compound of formula (I) by reaction with an enzyme, agastric acid, or the like, in the living body. Examples of the prodrugfor the compound of formula (I) include a compound wherein amino of thecompound of formula (I) is substituted with acyl, alkyl, phosphoricacid, or the like (e.g., a compound wherein amino of the compound offormula (I) is substituted with eicosanyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethy, tert-butyl, etc.); acompound wherein hydroxyl of the compound of formula (I) is substitutedwith acyl, alkyl, phosphoric acid, boric acid, or the like (e.g., acompound wherein hydroxyl of the compound of formula (I) is modifiedwith acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl, etc.); a compound wherein carboxyl of thecompound of formula (I) is modified with ester, amide, or the like(e.g., a compound wherein carboxyl of the compound of formula (I) ismodified with ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide, etc.), and the like.These compounds may be prepared by per se known method. In addition, theprodrug for the compound of formula (I) may hydrate or non-hydrate. Inaddition, the prodrug for the compound of formula (I) may be a compoundwhich is converted into the compound of formula (I) under thephysiological conditions as described in Pharmaceutical Research andDevelopment, Vol. 7 “Molecular Design”, pages 163-198 published in 1990by Hirokawa Publishing Co. In addition, compound (I) may be labeled withan isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc.) and the like.

In formula (I) of the present invention, any of each definitionrepresented by ring A, ring B, ring D, J, G, R^(D), R^(n) and E ispreferred. In the following, preferred groups, and preferred rings willbe listed. The symbols used herein have the same meanings as describedabove.

The “cyclic group” in the “cyclic group which may be substituted”represented by ring A is preferably, for example, a carbocyclic ring, aheterocyclic ring, or the like; more preferably, for example, the “C3-15monocyclic, bicyclic or tricyclic carbocyclic ring”, “3- to 15-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, or the like; especially preferably, for example,benzene, naphthalene, pyridine, pyrazole, dioxaindane, benzodioxane,cyclopropane, cycloheptane, cyclohexane, furan, thiophene,tetrahydrofuran, piperidine, morpholine, pyridin-1-oxide,1-methylpyridinium rings, or the like; and most preferably, benzene,naphthalene, pyridine, pyrazole, dioxaindane, benzodioxane rings, or thelike.

The “substituent” in the “cyclic group which may be substituted”represented by ring A is preferably, for example, halogen,trifluoromethyl, an aliphatic hydrocarbon group which may besubstituted, —OR^(a1), —NR^(a1)R^(a2), an 3- to 15-membered cyclic groupwhich may be substituted or the like; more preferably, for example,halogen, C1-8 alkyl which may be substituted, hydroxyl, amino, —O—(C1-8alkyl) which may be substituted with —NR^(b1)R^(b2), or the like;especially preferably, for example, halogen, C1-4 alkyl which may besubstituted, hydroxyl, amino, —O—(C1-4 alkyl) which may be substitutedwith —NR^(b1)R^(b2), or the like; and most preferably, for example,fluorine, chlorine, methyl, hydroxyl, methoxy, 2-dimethylaminoethyloxy,amino, or the like.

The “cyclic group” in the “cyclic group which may be substituted”represented by ring B is preferably, for example, a carbocyclic ring, aheterocyclic ring, or the like; and more preferably, for example, the“C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring”, the “3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, or the like. Examples include benzene, pyridine,thiophene, naphthalene, pyrrole, pyrazole, isoxazole, thiazole,benzothiadiazole, benzothiophene, imidazole, benzofuran, furan,benzopyran rings, and the like. The “C3-15 monocyclic, bicyclic ortricyclic carbocyclic ring” or the “3- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s)” isespecially preferably, for example, the “C3-8 monocyclic carbocyclicring” or the “3- to 8-membered monocyclic heterocyclic ring having 1 to4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, or the like. Among these, preferred examples includethe “C3-8 monocyclic aromatic carbocyclic ring”, the “3- to 8-memberedmonocyclic aromatic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s)”, and thelike. Specific examples include benzene, pyridine, thiophene, furan,pyrrole, pyrazole, isoxazole, thiazole rings, and the like, andespecially preferred examples include benzene, pyridine, thiophenerings, and the like.

The “substituent” in the “cyclic group which may be substituted”represented by ring B is preferably, for example, a substituent selectedfrom the above-described Group I, an aliphatic hydrocarbon group whichmay be substituted, a substituent selected from the above-describedGroup H, an carbamoyl which may be substituted, or the like; morepreferably, for example, an aliphatic hydrocarbon group which may besubstituted, halogen, nitro, trifluoromethyl, trifluoromethoxy,—OR^(a1), —NR^(a1)R^(a2), —SO₂R^(a1), —SR^(a1), —COOR^(a1), —COR^(a1) orthe like; especially preferably, for example, C1-8 alkyl, halogen,nitro, trifluoromethyl, or the like; and most preferably, for example,methyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, or thelike.

The “cyclic group” in the “cyclic group which may be substituted”represented by ring D is preferably, for example, a carbocyclic ring, aheterocyclic ring, or the like; more preferably, for example, the “3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s)”, or the like; and especially preferably, for example, a3- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s), or the like. The “3- to 10-membered monocyclic orbicyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s)” is preferably, forexample, “3- to 10-membered monocyclic or bicyclic heterocyclic ringhaving 1 to 4 nitrogen atoms as a hetero atom(s)”, or the like; morepreferably, for example, “3- to 10-membered monocyclic or bicyclicheterocyclic ring containing 1 or 2 nitrogen atoms as a hetero atom(s)”,or the like; especially preferably, for example,

or the like; and most preferably, for example,

or the like.

The “substituent” in the “cyclic group which may be substituted”represented by ring D is preferably, for example, an aliphatichydrocarbon group which may be substituted, halogen, cyano,trifluoromethyl, —COOR^(a1), an 3- to 15-membered cyclic group which maybe substituted, or the like; more preferably, for example, C1-8 alkyl,halogen, trifluoromethyl, a C3-10 monocyclic or bicyclic carbocyclicring which may be substituted, or the like; and especially preferably,for example, methyl, chlorine, bromine, trifluoromethyl, a benzene ringwhich may be substituted, or the like.

G is preferably, for example, a spacer having 1 to 4 atoms in its mainchain, or the like; more preferably, for example, a spacer having 1 to 4atoms in its main chain and containing at least one nitrogen, or thelike; and especially preferably, for example, —NR^(T1)—, —NR^(T1)—SO₂—,—NR^(T1)—CO—, —NR^(T1)—CO—NR^(T1)—, —NR^(T1)—SO₂—NR^(T2), —NR^(T1)—COO—,—NR^(T1)—O—, —NR^(T1)—NR^(T2)—, —NR^(T1)—W—,- SO₂—NR^(T1)—,—CO—NR^(T1)—, —OCO—NR^(T1)—, —O—NR^(T1)—, —W—NR^(T1)—, or the like.Among these, —NR^(T1)—SO₂— (wherein the nitrogen is bound to ring D, andthe sulfur atom is bound to ring B), especially, for example, —NH—SO₂—(wherein the nitrogen is bound to ring D, and the sulfur is bound toring B), is preferred.

J is preferably, for example, a spacer having 1 to 8 atoms in its mainchain, or the like; more preferably, for example, a spacer having 1 to 8atoms in its main chain and containing at least one oxygen atom, or thelike; and especially preferably, for example, those in which the oxygenatom is bound to ring D. More specifically, J is preferably, forexample,

wherein all symbols have the same meanings as described above, and thelike. Herein, R³ and R⁴ are each preferably, for example, hydrogen,methyl, or the like. E is preferably, for example, a bond, C1-6alkylene, C1-5 alkyleneoxy, or the like; more preferably, for example, abond, C1-4 alkylene, C1-3 alkyleneoxy, or the like; and especiallypreferably, for example, a bond, methylene, methylenoxy, or the like. Asfor E, more preferred is one that the oxygen in C1-5 alkyleneoxy whichis described as a preferred group, C1-3 alkyleneoxy which is describedas a more preferred group or methylenoxy which is described as mostpreferred group, is bound to ring A.

In the present invention, preferred is the compound of formula (I)comprising a combination of the above-described preferred groups andpreferred rings. Especially, the compound of formula (A) is preferred.

In formula (A), any of each definition represented by R¹, R², R³, R⁴,R⁵, R⁶, E¹, ring A¹, ring B¹, p and q is preferred. In the following,preferred groups, and preferred rings will be listed. The symbols usedherein have the same meanings as described above.

Ring A¹ is preferably, for example, “C3-10 monocyclic or bicycliccarbocyclic ring”, “3- to 10-membered monocyclic or bicyclicheterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s)”, or the like; morepreferably, for example, “C3-10 monocyclic or bicyclic carbocyclicaryl”, “3- to 10-membered monocyclic or bicyclic heterocyclic arylhaving 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfuratoms as a hetero atom(s) or partially or completely saturated onethereof”, or the like; and especially preferably, for example, benzene,naphthalene, pyridine, pyrazole, dioxaindane, benzodioxane rings, or thelike.

R⁵ is preferably, for example, halogen, C1-8 alkyl, —OR³¹, —NR³²R³³, orthe like; more preferably, for example, halogen, C1-4 alkyl, hydroxyl,C1-4 alkoxy, C1-4 alkyloxy substituted with —NR³⁷R³⁸, amino, or thelike; and especially preferably, for example, chlorine, methyl,hydroxyl, methoxy, 2-dimethylaminoethyloxy, amino, or the like.

-   -   p is preferably 0, 1 or 2.

Ring B¹ is preferably, for example, “C3-8 monocyclic carbocyclic ring”,“3- to 8-membered monocyclic heterocyclic ring having 1 to 4 nitrogenatoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a heteroatom(s)”, or the like; more preferably, for example, “C3-8 monocycliccarbocyclic aryl”, “3- to 8-membered monocyclic heterocyclic aryl having1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms asa hetero atom(s)”, or the like; and especially preferably, for example,benzene, pyridine, thiophene, or the like.

R⁶ is preferably, for example, the other substituents than Cyc2 amongthe above-described substituents as R⁶; more preferably, for example,C1-8 alkyl, halogen, or the like; especially preferably, for example,C1-4 alkyl, halogen, or the like, and most preferably, for example,methyl, fluorine, chlorine or bromine, or the like.

-   -   q is preferably 0, 1 or 2.

R¹ and R² are each preferably, for example, hydrogen, C1-8 alkyl,halogen, trifluoromethyl, cyano, Cyc1, or the like; more preferably, forexample, hydrogen, C1-4 alkyl, halogen, trifluoromethyl, cyano or “C3-15monocyclic, bicyclic or tricyclic carbocyclic ring”, or the like; andespecially preferably, for example, hydrogen, methyl, chlorine orbromine, trifluoromethyl, cyano, a benzene ring, or the like.Furthermore, R¹ and R² also preferably form —CH═CH—CH═CH—, together witheach other.

Cyc1 is preferably, for example, “C3-8 monocyclic carbocyclic ring”, “3-to 8-membered monocyclic heterocyclic ring having 1 to 4 nitrogen atoms,1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s)”, orthe like; and more preferably, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, benzene, imidazole, pyridine, piperidine,morpholine, or the like.

R¹⁸ as a substituent of Cyc1 is preferably, for example, —NR²¹R²²,—COR²³, or the like; and especially preferably, for example, —NH₂ or—CHO, or the like.

R³ and R⁴ are each preferably, for example, hydrogen, methyl, or thelike.

E¹ is preferably, for example, a single bond, C1-4 alkylene, C1-3alkyleneoxy; and especially preferably, for example, a single bond,methylene, methylenoxy, or the like.

The compound of the present invention of formula (I), especially, thecompound of the present invention of formula (A) is preferably thecompound of formula (A) comprising a combination of the above-describedpreferred groups and preferred rings among the present compound offormula (A).

Examples of the preferred compound of the present invention include thecompounds described in Examples or salts thereof.

The compound of the present invention of formula (I), especially, thecompound of the present invention of formula (A) is preferably, forexample, a pyrazine derivative or a salt thereof of formula (I-1):

wherein R¹ and R² have the same meanings as described above, formula(I-2):

wherein R¹ and R² have the same meanings as described above, formula(I-3):

wherein R¹ and R² have the same meanings as described above, formula(I-4):

wherein R₁ and R² have the same meanings as described above, formula(I-5):

wherein R¹ and R² have the same meanings as described above, formula(I-6):

wherein R¹ and R² have the same meanings as described above, formula(I-7):

wherein R¹ and R² have the same meanings as described above, formula(I-8):

wherein R¹ and R² have the same meanings as described above, formula(I-9):

wherein R¹ and R² have the same meanings as described above, formula(I-10):

wherein R¹ and R² have the same meanings as described above, formula(I-11):

wherein R¹ and R² have the same meanings as described above, formula(I-12):

wherein R¹ and R² have the same meanings as described above, formula(I-13):

wherein R¹ and R² have the same meanings as described above, formula(I-14):

wherein R¹ and R² have the same meanings as described above, formula(I-15):

wherein R¹ and R² have the same meanings as described above, formula(I-16):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-17):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-18):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-19):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-20):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-21):

wherein E¹, ring A⁵ and p have the same meanings as described above,formula (I-22):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-23):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-24):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-25):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-26):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-27):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-28):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,formula (I-29):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above,and formula (I-30):

wherein E¹, ring A¹, R⁵ and p have the same meanings as described above.

Examples of the compound of the present invention include the compoundsshown in the following Tables 1 to 30, the compounds described inExamples, and salts thereof. TABLE 1 (I-1)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 2 (I-2)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 3 (I-3)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 4 (I-4)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 5 (I-5)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 6 (I-6)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 7 (I-7)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 8 (I-8)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 9 (I-9)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 10 (I-10)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 11 (I-11)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 12 (I-12)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 13 (I-13)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 14 (I-14)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 15 (I-15)

No. R¹ R² 1 H H 2 CH₃ H 3 OCH₃ H 4 Cl H 5 Br H 6 Ph H 7 CN H 8 NO₂ H 9COOH H 10 —(CH₂)₃— 11 H CH₃ 12 H OCH₃ 13 H Cl 14 H Br 15 H Ph 16 H CN 17H NO₂ 18 H COOH 19 —(CH₂)₄— 20 —CH═CH—CH═CH—

TABLE 16 (I-16)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 17 (I-17)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 18 (I-18)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 19 (I-19)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 20 (I-20)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 21 (I-21)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 22 (I-22)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 23 (I-23)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 24 (I-24)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 25 (I-25)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 26 (I-26)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 27 (I-27)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 28 (I-28)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 29 (I-29)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 30 (I-30)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Furthermore, in the compounds represented by formula (I-1) to (I-30) aspreferable compounds or specific compounds, the substituent representedby

is preferably substituted with (thiophen-2-yl)sulfonylamino,(2,3-dichlorothiophen-5-yl)sulfonylamino,(2,5-dichlorothiophen-3-yl)sulfonylamino,2,3-dichlorophenylsulfonylamino, 2-methyl-3-chlorophenylsulfonylamino,2-trifluoromethylphenylsulfonylamino, 2-chlorophenylsulfonylamino,2-bromophenylsulfonylamino, 2-chloro-4-fluorophenylsulfonylamino,2,6-dichlorophenylsulfonylamino, 3-bromophenylsulfonylamino,2,4-difluorophenylsulfonylamino, 2-methylphenylsulfonylamino,3-chloro-4-methylphenylsulfonylamino, 3-chlorophenylsulfonylamino,2-fluorophenylsulfonylamino, 2,3,4-trichlorophenylsulfonylamino,2,4-dichlorophenylsulfonylamino, 2,6-difluorophenylsulfonylamino,2-cyanophenylsulfonylamino, 2,4,6-trichlorophenylsulfonylamino,phenylsulfonylamino, 3-nitro-4-methylphenylsulfonylamino,3-nitrophenylsulfonylamino, 4-bromophenylsulfonylamino,3-methylphenylsulfonylamino, 2,5-difluoro-4-bromophenylsulfonylamino,3-trifluoromethylphenylsulfonylamino,2-trifluoromethoxyphenylsulfonylamino, 3-methoxyphenylsulfonylamino,4-chloro-2,5-dimethylphenylsulfonylamino,2,4-dichloro-6-methylphenylsulfonylamino,4-trifluoromethyl-2-chlorophenylsulfonylamino,2-methyl-4-fluorophenylsulfonylamino,3-nitro-4-chlorophenylsulfonylamino,2-methoxycarbonylphenylsulfonylamino,2-methoxy-5-methylphenylsulfonylamino, 4-ethylphenylsulfonylamino,2,5-dichlorophenylsulfonylamino, 4-trifluoromethoxysulfonylamino,2,4,5-trichlorophenylsulfonylamino, 4-(2-propyl)phenylsulfonylamino,4-(2-methoxyphenyloxy)phenylsulfonylamino,2-nitro-4-methoxyphenylsulfonylamino, 4-nitrophenylsulfonylamino,2,5-dimethoxyphenylsulfonylamino, 2-methyl-5-nitrophenylsulfonylamino,4-butoxyphenylsulfonylamino, 2-methoxy-4-methylphenylsulfonyiamino,2-methoxy-5-butylphenylsulfonylamino, 3,5-dimethylphenylsulfonylamino,2,3,6-trimethyl-4-methoxyphenylsulfonylamino;2-methoxy-5-chlorophenylsulfonylamino,2,4,6-trimethylphenylsulfonylamino, or 4-methoxyphenylsulfonylamino.Method of Producing the Compound of the Present Invention

A compound of formula (I) may be prepared by combining known methods,for Example, a method shown below, methods described in Examples, ormethods described in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2^(nd) Edition (Richard C. Larock, JohnWiley & Sons Inc., 1999, or other methods.

Among the compounds of the present invention of formula (I), a compoundin which J is bound to ring D via an oxygen atom, i.e., a compound offormula (I-A):

wherein J¹ represents a bond or a spacer having 1 to 7 atoms in its mainchain, and other symbols have the same meanings as described above;can be prepared by a method of (a-1) or (b-1) shown below.(a-1): A Compound of the Present Invention of Formula (I-A) can bePrepared by Subjecting a Compound of Formula (II):

wherein all symbols have the same meanings as described above; and acompound represented by formula (III):

wherein X represents a leaving group (e.g., halogen, methanesulfonyloxy(OMs), p-toluenesulfonyloxy (OTs), trifluoromethanesulfonyloxy (OTf),etc.), and other symbols have the same meanings as described above;to etherification, and if necessary, to deprotection reaction and/or tocleavage reaction from a resin.

The etherification is carried out by a known method, for Example, byreacting in an organic solvent (N,N-dimethylformamide,dimethylsulfoxide, chloroform, methylene chloride, diethyl ether,tetrahydrofuran, methyl t-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane,etc.) in the presence of a base [alkali metal hydride (sodium hydride,potassium hydride, etc.), organometal reagent (N-butyl lithium, etc.),quaternary ammonium salt (tetrabutylammonium fluoride, etc.), or thelike] at 0 to 120° C.

The compound of formula (I-A) wherein at least one group has carboxyl,hydroxyl, amino or thiol can be prepared by subjecting the compound inwhich the respective groups are protected, to deprotection reaction.

A protective group for carboxyl includes, for Example, methyl, an ethyl,an allyl, t-butyl, trichloroethyl, benzyl (Bn), phenacyl, and the like.

A protective group for hydroxyl includes, for Example, methyl, trityl,methoxymethyl (MOM), 1-ethoxyethyl(EE), methoxyethoxymethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac),pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like.

A protective group for amino includes, for Example, benzyloxycarbonyl,t-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluororenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), and thelike.

A protective group for thiol includes, for Example, benzyl,methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP),diphenylmethyl and acetyl (Ac).

A protective group for carboxyl, hydroxyl, amino or thiol is notparticularly limited in addition to the above-described groups as longas it can be deprotected easily and selectively. For Example, thosedescribed in Protective Groups in Organic Synthesis (T. W. Greene, JohnWiley & Sons Inc., 1999) may be used.

The deprotection of the protective group for carboxyl, hydroxyl, aminoor thiol is well known. For Example, it is

-   (1) alkaline hydrolysis,-   (2) deprotection of a protective group in acidic conditions,-   (3) deprotection of a protective group by hydrogenolysis,-   (4) deprotection of a protective group containing silyl,-   (5) deprotection of a protective group using a metal,-   (6) deprotection of a protective group using an organometal,    and the like.

In the following, these methods are specifically described:

-   (1) The deprotection of the protective group by alkaline hydrolysis    condition may be carried out, for Example, in an organic solvent    (methanol, tetrahydrofuran, 1,4-dioxane, etc.) with alkaline metal    hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide,    etc.), alkaline earth metal hydroxide (barium hydroxide, calcium    hydroxide, etc.), carbonate (sodium carbonate or potassium    carbonate, etc.), an aqueous solution thereof or a mixture thereof    at 0 to 40° C.-   (2) The deprotection of the protective group in acidic conditions    may be carried out, for Example, in an organic solvent (methylene    chloride, chloroform, 1,4-dioxane, ethyl acetate, anisole; etc.),    organic acid (acetic acid, trifluoroacetic acid, methanesulfonic    acid, p-toluenesulfonic acid, etc.), inorganic acid (hydrochloric    acid, sulfuric acid, etc.), or a mixture thereof (hydrogen    bromide/acetic acid, etc.) at 0 to 100° C.-   (3) The deprotection of the protective group by hydrogenolysis may    be carried out, for Example, in a solvent (ethers (tetrahydrofuran,    1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc.), alcohols    (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.),    ketones (acetone, methylethylketone, etc.), nitriles (acetonitrile,    etc.), amides (N,N-dimethylformamide, etc.), water, ethyl acetate,    acetic acid, a mixture of two or more thereof, etc.) in the presence    of a catalyst (palladium on carbon, palladium black, palladium    hydroxide, platinum oxide, Raney nickel, etc.) under hydrogen    atmosphere at a normal pressure or elevated pressure, or in the    presence of ammonium formate at 0 to 200° C.-   (4) The deprotection of the protective group for silyl may be    carried out, for Example, in an organic solvent (tetrahydrofuran,    acetonitrile, etc.), with fluoride (tetrabutylammonium fluoride, an    aqueous solution of hydrofluoride, hydrofluoride-pyridine complex,    etc.) at −20 to 40° C.-   (5) The deprotection of the protective group a using metal may be    carried out, for Example, in an acidic solvent (acetic acid, a pH    4.2 to 7.2 buffer, a mixed solution of the buffer and an organic    solvent such as tetrahydrofuran, etc.) in the presence of powder    zinc, with or without an ultrasonic wave at a temperature of 0 to    40° C.-   (6) The deprotection of the protective group using a metal complex    may be carried out, for Example, in an organic solvent (methylene    chloride, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate,    acetonitrile, 1,4-dioxane, ethanol, etc.), water or a mixed solvent    thereof in the presence of a trap reagent (tributyltin hydride,    triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine,    etc.), an organic acid (acetic acid, formic acid, 2-ethylhexanic    acid, etc.) and/or an organic acid salt (sodium 2-ethylhexanate,    potassium 2-ethylhexanate, etc) in the presence or absence of a    phosphine reagent (triphenylphosphine, etc.) using a metal complex    (tetrakis(triphenylphosphine)palladium (O),    dichlorobis(triphenylphosphine)palladium (II), palladium acetate    (II), chlorotris(triphenylphosphine)rhodium (I), etc.) at 0 to 40°    C.

In addition to the above methods, the deprotection may be carried out bythe method described in Protective Groups in Organic Synthesis (T. W.Greene, John Wiley & Sons Inc., 1999).

Furthermore, if the compound has a moiety to bind to a resin in themolecule, and the resin is a polystyrene resin, the compound of thepresent invention can be cleaved from the resin by the following method.The cleavage reaction from the resin may be carried out by a knownmethod, for Example, by reacting in an organic solvent (methylenechloride, 1,2-dichloroethane, toluene, etc.), with acid (acetic acid,trifluoroacetic acid, hydrochloric acid, etc.) at 0 to 100° C.

As well understood to the skilled persons in the art, the objectivecompounds of the present invention may be prepared easily by using thesedeprotection reactions.

Furthermore, if necessary, after those reactions, a procedure ofconverting the compound into the objective non-toxic salts may becarried out according to a known method.(b-1): A Compound of the Present Invention of Formula (I-A) can bePrepared by Subjecting a Compound of Formula (IV):

wherein all symbols have the same meanings as described above; and acompound of formula (V):

wherein all symbols have the same meanings as described above;to the same reaction as those in above-described (a-1), and ifnecessary, to deprotection reaction and/or to cleavage reaction from aresin. The deprotection of the protective group can be carried out inthe same manner as those in the above-described method. Furthermore, ifthe compound has a moiety to bind to a resin in the molecule, and theresin is a polystyrene resin, the compound of the present invention canbe cleaved from the resin in the same manner as those in theabove-described method.

Among the compounds of the present invention of formula (I), a compoundin which G is bound to ring D via —NHSO₂—, i.e., a compound of formula(I-B):

wherein G¹ represents a bond or a spacer having 1 or 2 atoms in its mainchain, and other symbols have the same meanings as described above;can be prepared by a method of (a-2) or (b-2) shown below.(a-2): A Compound of the Present Invention of Formula (I-B) can bePrepared by Subjecting a Compound of Formula (VI):

wherein all symbols have the same meanings as described above, and acompound of formula (VII):

wherein all symbols have the same meanings as described above; tosulfonamidation.

The sulfonamidation may be carried out, for Example, by reacting in anorganic solvent (chloroform, methylene chloride, 1,2-dichloroethane,diethyl ether, tetrahydrofuran, etc.) in the presence of a base(diisopropylethylamine, pyridine, triethylamine, N,N-dimethylaniline,N,N-dimethylaminopyridine, sodium hydride, potassium hydride, etc.) at 0to 40° C.

The compound of formula (I-B) wherein at least one group containscarboxyl, hydroxyl, amino or thiol can be prepared by subjecting thecompound in which the respective groups are protected, to deprotectionreaction. The deprotection of the protective group can be carried out inthe same manner as those in the above-described method. Furthermore, ifthe compound has a moiety to bind to a resin in the molecule, and theresin is a polystyrene resin, the compound of the present invention canbe cleaved from the resin in the same manner as those in theabove-described method.(b-2): A Compound of the Present Invention of Formula (I-B) can bePrepared by Subjecting a Compound of Formula (VIII):

wherein all symbols have the same meanings as described above; and acompound represented by formula (IX):

wherein all symbols have the same meanings as described above; toreaction, and if necessary, to deprotection reaction and/or to cleavagereaction from a resin.

This reaction may be carried out by a known method, for Example, byreacting in an organic solvent (N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, etc.) in the presence orabsence of a base (potassium carbonate, cesium carbonate, triethylamine,N-butyl lithium, sodium hydride, sodium hydroxide, etc.) at 0 to 200° C.

The deprotection of the protective group can be carried out in the samemanner as those in the above-described method. Furthermore, if thecompound has a moiety to bind to a resin the molecule, and the resin isa polystyrene resin, the compound of the present invention can becleaved from the resin in the same manner as those in theabove-described method.

Among the compounds of the present invention of formula (I), a compoundin which G is bound to ring D via —NHCO—, i.e., a compound of formula(I-C):

wherein all symbols have the same meanings as described above;can be prepared by subjecting a compound of formula (VI) and a compoundrepresented by formula (X):

wherein all symbols have the same meanings as described above;to amidation, and if necessary, to deprotection reaction and/or tocleavage reaction from a resin.

The amidation is well known, and it includes, for Example,

-   (1) a method using an acyl halide,-   (2) a method using a mixed acid anhydride, and-   (3) a method using a condensing agent, and the like.

In the following, these methods are explained in detail.

-   (1) The method using an acyl halide may be carried out, for Example,    by reacting carboxylic acid with acyl halide (e.g., oxalyl chloride,    thionyl chloride, etc.) in an organic solvent (e.g., chloroform,    methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without    a solvent at −20° C. to reflux temperature. And then the obtained    acyl halide derivative may be reacted with amine in an inert organic    solvent (e.g., chloroform, methylene chloride, diethyl ether,    tetrahydrofuran, etc.) in the presence of a base (e.g., pyridine,    triethyl amine, N,N-dimethyl aniline, N,N-dimethylaminopyridine,    diisopropylethylamine, etc.) at 0 to 40° C. Alternatively, the    obtained acyl halide derivative may be reacted with amine in an    organic solvent (e.g., 1,4-dioxane, tetrahydrofuran, etc.) using an    alkaline aqueous solution (e.g., sodium bicarbonate, sodium    hydroxide, etc.) at 0 to 40° C.-   (2) The method using a mixed acid anhydride may be carried out, for    Example, by reacting carboxylic acid with acyl halide (e.g.,    pivaloyl chloride, p-toluenesulfonyl chloride, methanesulfonyl    chloride, etc.) or an acid derivative (e.g., ethyl chloroformate,    isobutyl chloroformate, etc.) in an organic solvent (e.g.,    chloroform, methylene chloride, diethyl ether, tetrahydrofuran,    etc.) or without a solvent in the presence of a base (e.g.,    pyridine, triethylamine, N,N-dimethylaniline,    N,N-dimethylaminopyridine, diisopropylethylamine, etc.) at 0 to    40° C. And then the obtained mixed acid anhydride derivative may be    reacted with amine in an organic solvent (e.g., chloroform,    methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0 to    40° C.-   (3) The method using a condensing agent may be carried out, for    Example, by reacting carboxylic acid with amine in an organic    solvent (e.g., chloroform, methylene chloride,    N,N-dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or    without a solvent in the presence or absence of a base (e.g.,    pyridine, triethylamine, N,N-dimethylaniline,    N,N-dimethylaminopyridine, etc.), using a condensing agent (e.g.,    1,3-dicyclohexyl carbodiimide (DCC), 4-ethyl-3-[3    (dimethylamino)propyl]carbodiimide (EDC),    1,3-diisopropylcarbodiimide (DIC), 1,1′-carbodiimidazole (CDI),    2-chloro-1-methylpyridinium iodide, 1-propanephosphonic acid cyclic    anhydride (PPA), etc.) in the presence or absence of    1-hydroxybenzotriazole (HOBt) at 0 to 40° C.

The reactions described in (1), (2) and (3) may be carried out under anatmosphere of an inert gas (e.g., argon, nitrogen, etc.) on anhydrouscondition.

The compound of formula (I-C) in which at least one group containscarboxyl, hydroxyl, amino or thiol can be prepared by subjecting thecompound in which the respective groups are protected, to deprotectionreaction. The deprotection of the protective group can be carried out inthe same manner as those in the above-described method. Furthermore, ifthe compound has a moiety to bind to a resin in the molecule, and theresin is a polystyrene resin, the compound of the present invention canbe cleaved from the resin in the same manner as those in theabove-described method.

Among the compounds of the present invention of formula (I), a compoundin which J is a bond or bound to ring D via carbon, i.e., a compound offormula (I-D):

wherein J² is the same as J, wherein the atoms which bind to the bond orring D are carbon atoms, and other symbols have the same meanings asdescribed above;can be prepared by a method of (a-3) or (b-3) shown below.(a-3): A Compound of the Present Invention of Formula (I-D) can bePrepared by Subjecting a Compound of Formula (IV) and a Compound ofFormula (XI):

wherein all symbols have the same meanings as described above;to reaction, and if necessary, to deprotection reaction and/or tocleavage reaction from a resin.

The reaction of the compound of formula (IV) and the compound of formula(XI) may be carried out by a known method, for Example, by reacting inan organic solvent (benzene, toluene, N,N-dimethylformamide,1,4-dioxane, tetrahydrofuran, methanol, acetonitrile,1,2-dimethoxyethane, acetone, etc.) in the presence of a base (sodiumethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodiumcarbonate, sodium hydrocarbonate, potassium carbonate, cesium carbonate,thallium carbonate, tripotassium phosphate, cesium fluoride, bariumhydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solutionthereof, or a mixture thereof and a catalyst(tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),dichlorobis(triphenylphosphine)palladium (Pd(Cl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,1-1′-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl₂(dppf)₂),dichlorodiallylpalladium (PdCl₂(allyl)₂),phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh₃)₂), etc.) at10 to 120° C.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.(b-3): A Compound of the Present Invention of Formula (I-D) can bePrepared by Subjecting the Compound of Formula (XII):

wherein all symbols have the same meanings as described above;and the compound of formula (XIII):

wherein all symbols have the same meanings as described above;to the same reaction as those above-described for the compound offormula (IV) and the compound of formula (XI), and if necessary, todeprotection reaction and/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which G is a bond or bound to ring D via carbon, i.e., a compound offormula (I-E):

wherein G² is the same as G, wherein G is a bond or the atom which bindsto ring D is carbon, and other symbols have the same meanings asdescribed above;can be prepared by a method of (a4) or (b4) shown below.(a4): A Compound of the Present Invention of Formula (I-E) can bePrepared by Subjecting a Compound of Formula (VIII) and a Compound ofFormula (XIV):

wherein all symbols have the same meanings as described above;to the same reaction as those above-described for the compound offormula (IV) and the compound of formula (XI), and if necessary, todeprotection reaction and/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.(b-4): A Compound of the Present Invention of Formula (I-E) can bePrepared by Subjecting a Compound of Formula (XV):

wherein all symbols have the same meanings as described above;and a compound of formula (XVI):

wherein all symbols have the same meanings as described above,to the same reaction as those above-described for the compound offormula (IV) and the compound of formula (XI), and if necessary, todeprotection reaction and/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D is C1-8, C2-8 alkenyl or C2-8alkynyl, i.e., a compound of formula (I-F):

wherein R^(F) represents C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, andother symbols have the same meanings as described above;can be prepared by subjecting a compound of formula (XVII):

wherein all symbols have the same meanings as described above;to alkylation reaction, and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The alkylation reaction may be carried out by a known method, forExample, by reacting in an organic solvent (tetrahydrofuran, diethylether, etc.) in the presence of an organometal reagent (methylmagnesiumbromide, n-butyl lithium, ethynylmagnesium bromide, etc.) and a catalyst([1,3-bis(diphenylphosphino)propane]dichloro nickel (II) (NiCl₂(dppp)),etc.) at 0 to 4⁰° C.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D is a cyclic group which may besubstituted, i.e., the compound of formula (I-G):

wherein R^(G) represents a cyclic group which may be substituted, andother symbols have the same meanings as described above;can be prepared by subjecting a compound of formula (XVII) and thecompound of formula (XVIII):R^(G)—B(OH)₂  (XVIII)wherein all symbols have the same meanings as described above;to the same reaction as those above-described for the compound offormula (IV) and the compound of formula (XI), and if necessary, todeprotection reaction and/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D represents COOR^(a1) and R^(a1)represents a group other than hydrogen, i.e., a compound of formula(I-H):

wherein R^(H) is the same as R^(a1) except hydrogen, and other symbolshave the same meanings as described above;can be prepared by subjecting a compound of formula (XVII) and acompound of formula (XIX)R^(H)—OH  (XIX)wherein all symbols have the same meanings as described above;to reaction under an atmosphere of carbon monoxide gas, and ifnecessary, to deprotection reaction and/or to cleavage reaction from aresin.

The reaction of the compound of formula (XVII) with the compound offormula (XIX) may be carried out by a known method, for Example, byreacting in an organic solvent (N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, etc.) in the presenceof a base (triethylamine, diisopropylethylamine, N-methylmorpholine,etc.) and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),dichlorobis(triphenylphosphine)palladium (PdCl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,1,1′-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl₂(dppf)₂),dichlorodiallylpalladium (PdCl₂(allyl)₂),phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh₃)₂), etc.) at10 to 120° C. under an atmosphere of carbon monoxide gas.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D is COOH, i.e., a compound offormula (I-I):

wherein all symbols have the same meanings as described above;can be prepared by a method of (a-5) or (b-5) shown below.(a-5): A Compound of the Present Invention of Formula (I-I) can bePrepared by Subjecting the Compound of Formula (I-H) to DeprotectionReaction.

The deprotection of the protective group can be carried out in the samemanner as those in the above-described method.(b-5): A compound of the Present Invention of Formula (I-I) can bePrepared by Subjecting a Compound of Formula (XVII) and2-trimethylsilylethanol of Formula (XX):

to reaction in the presence of carbon monoxide gas, and if necessary, todeprotection reaction and/or to cleavage reaction from a resin.

The reaction between the compound of formula (XVII) and the compound offormula (XX) may be carried out in the same manner as thoseabove-described in the reaction between the compound of formula (XVII)and the compound of formula (XIX).

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D represents CONR^(a1)R^(a2), i.e.,a compound of formula (I-J):

wherein all symbols have the same meanings as described above;can be prepared by subjecting the compound of formula (I-I) prepared byabove-described method and the compound of formula (XXI):

wherein all symbols have the same meanings as described above;to amidation which is the same reaction used for synthesizing thecompound of formula (I-C), and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (I), a compoundin which one of substituents in ring D is CH₂OH, i.e., a compound offormula (I-K):

wherein all symbols have the same meanings as described above;can be prepared by subjecting the compound of formula (I-H) or thecompound of formula (I-I) which was prepared by above-described method,to reduction reaction, and if necessary, to deprotection reaction and/orto cleavage reaction from a resin.

The reduction reaction may be carried out by a known method, forExample, by reacting in an organic solvent (tetrahydrofuran, diethylether, etc.) in the presence of a reducing agent (sodium borohydride,lithium borohydride, aluminum lithium hydride, diisobutyl aluminumhydride, a boran-dimethylsulfide complex, etc.) at −20 to 100° C.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (II), a compoundin which G is bound to ring D via —NHSO₂—, i.e., a compound of formula(II-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting a compound represented by formula (XXII):

wherein X¹ is the same as X, and other symbols have the same meanings asdescribed above;and the compound of formula (IX) to the same reaction as thoseabove-described in (b-2) and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (IV), a compoundin which G is bound to ring D via —NHSO₂—, i.e., a compound of formula(IV-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting a compound represented by formula (XXIII):

wherein all symbols have the same meanings as described above;and the compound of formula (IX) to the same reaction as thoseabove-described in (b-2) and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (XII), acompound in which G is bound to ring D via —NHSO₂—, i.e., a compound offormula (XII-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting a compound of formula (XXIV):

wherein all symbols have the same meanings as described above;and the compound of formula (IX) to the same reaction as thoseabove-described in (b-2) and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (VI), a compoundin which J is bound to ring D via oxygen, i.e., a compound of formula(VI-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting a compound of formula (XXV):

wherein all symbols have the same meanings as described above;and the compound of formula (V) to the same reaction as thoseabove-described in (a-1) and if necessary, to deprotection reactionand/or to cleavage reaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (VIII), acompound in which J is bound to ring D via an oxygen atom, i.e., acompound of formula (VIII-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting the compound of formula (XXIII) and thecompound of formula (V) to the same reaction as those above-described in(a-1) and if necessary, to deprotection reaction and/or to cleavagereaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Among the compounds of the present invention of formula (XV), a compoundin which J is bound to ring D via an oxygen atom, i.e., a compound offormula (XV-B):

wherein all symbols have the same meanings as described above;can be prepared by subjecting the compound of formula (XXIV) and thecompound of formula (V) to the same reaction as those above-described in(a-1) and if necessary, to deprotection reaction and/or to cleavagereaction from a resin.

The deprotection reaction and the cleavage reaction from the resin canbe carried out in the same manner as those in the above-describedmethod.

Other compounds of formulae (II) to (XXV) used as starting materials orreagents are known per se or may be prepared by known methods, forExample, or methods described in Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2^(nd) Edition (Richard C.Larock, John Wiley & Sons Inc., 1999).

In each reaction in the present specification, as apparent to theskilled persons in the art, the reactions involving heating may becarried out using a water bath, an oil bath, a sand bath or a microwave.

In each reaction in the present specification, a solid-supported reagentwhich is supported on a high molecular polymer (e.g., polystyrene,polyacrylamide, polypropylene, polyethylene glycol, etc.) may besuitably used.

In each reaction in the present specification, the reaction products maybe purified by a conventional purification method, for Example, bydistillation at a normal or reduced pressure, high performance liquidchromatography using silica gel or magnesium silicate, thin layerchromatography, ion-exchange resin, scavenger resin, columnchromatography, washing or recrystallization. The purification may bedone after each reaction or after several reactions.

In the reactions using a polystyrene resin in the present specification,the reaction products may be purified by a conventional purificationmethod, for Example, by washing with a solvent (N,N-dimethylformamide,methylene chloride, methanol, tetrahydrofuran, toluene, aceticacid/toluene, etc.) several times.

Pharmacological Activities

Pharmacological tests in addition to those described in ExperimentalExamples include the followings. As shown below, CCR4 antagonisticactivity in vitro of the compound of the present invention can bedemonstrated, and also efficacy in vivo can be confirmed.

As a system for screening a CCR4 antagonist, for Example, a system formeasuring effects for the transient increase of Ca ions induced bymediation of CCR4 ligands other than MDC, for Example, TARC, etc. can beconducted since CCR4 is a seven transmembraneous G protein-coupled typereceptor. Furthermore, CCR4 antagonistic activity also can bedemonstrated by the method described in WO2002/30357, WO2002/30358 orWO2002/94264, or a modification thereof, and these methods can be alsoused as a screening method. Furthermore, these publications alsodisclose experimental methods using animals, and therefore according tothe methods or a modification thereof, the efficacy of a CCR4 antagonistin vivo model can be confirmed.

Toxicity

The toxicity of the compound of the present invention is very low, andit is believed that the compound is safe enough for pharmaceutical use.

INDUSTRIAL APPLICABILITY

Application to Pharmaceuticals

Since the compound of the present invention of formula (I) has CCR4antagonistic activity in animals including human, especially human, itis considered that it is useful as a preventive and/or therapeutic agentfor diseases associated with CCR4, i.e., CCR4-mediated diseases such asinflammatory and/or allergic diseases [e.g., systemic inflammatoryresponse syndrome (SIRS), anaphylaxis or anaphylaxis-like reaction,allergic vasculitis, organ graft rejection, hepatitis, nephritis,nephrosis, pancreatitis, rhinitis, arthritis, inflammatory oculardiseases (e.g., conjunctivitis, etc.), inflammatory bowel diseases(e.g., ulcerative colitis, Crohn's disease, eosinophilicgastroenteropathy, etc.), diseases in cerebro and/or circulatory system(e.g., atherosclerosis, thrombosis, ischemic/reperfusion disorders,restenosis, infarction, etc.), respiratory diseases (e.g., acuterespiratory distress syndrome (ARDS), asthma, allergic broncho-pulmonaryaspergillosis, etc.), dermatic diseases [e.g., dermatitis (e.g., atopicdermatitis, psoriasis, contact dermatitis, eczema, urticaria, pruritis,etc.), and the like], autoimmune diseases (e.g., multiple sclerosis,chronic rheumatoid arthritis, systemic erythematosus, Type I diabetesmellitus, glomerular nephritis, Sjogren's syndrome, etc.), metabolismand/or endocrinologic diseases (e.g., diabetes mellitus, etc.), cancerdiseases [for Example, malignant neoplasm (e.g., leukemia, cancer andcancer metastasis, etc.), and the like], infections [for Example, viraldiseases (e.g., acquired immunodeficiency syndrom, severe acuterespiratory syndrome (SARS), and the like], and the like.

Furthermore, the compound of the present invention represented byformula (I) has activity of regulating a TNFα amount in the living body,especially in the blood, i.e., activity of regulating TNFα, morespecifically, activity of suppressing TNFα production. In addition, thecompound of the present invention has activity of inhibiting theeffector cell functions (e.g., migration, etc.) of expressing CCR4,i.e., inhibitory activity for effector cell functions. Therefore, thecompound of the present invention is considered to be useful as apreventive and/or therapeutic agent for diseases which is suggested tobe associated with CCR4, and diseases which is suggested to beassociated with the effector cells, especially the above-describeddisease group.

A combination agent obtained by combining the compound of formula (I) ora non-toxic salt thereof with other medicaments may be administered toaccomplish the following purposes:

-   1) to supplement and/or enhance the preventive and/or therapeutic    effect of the present compound;-   2) to improve the kinetics and/or absorption and reduce the dose of    the present compound; and/or-   3) to eliminate the side effects of the present compound; and    in addition, (1) to supplement and/or enhance the preventive and/or    therapeutic effect of the other medicaments used in combination; (2)    to improve the kinetics and/or absorption and reduce the dose of the    other medicaments used in combination; and/or (3) to eliminate the    side effects of the other medicaments used in combination.

A combination of the compound of formula (I) and other medicaments maybe administered in the form of the formulations having these componentsincorporated in one preparation, or may be administered in separatepreparations. In the case where these medicaments are administered inseparate preparations, they may be administered simultaneously or atdifferent times. In the latter case, the compound of formula (I) may beadministered before the other medicaments. Alternatively, the othermedicaments may be administered before the compound of formula (I). Themethod for the administration of these medicaments are the same ordifferent.

The diseases on which the preventive and/or therapeutic effect of theabove mentioned combination preparations works are not specificallylimited but may be those for which the preventive and/or therapeuticeffect of the compound represented by formula (I) is supplemented and/orenhanced.

The weight ratio of the compound of formula (I) and the othermedicaments is not specifically limited.

Any combination of two or more other medicaments may be administered.

Furthermore, the other medicaments for supplementing and/or enhancingthe preventive and/or therapeutic effect of the compound of formula (I)include not only those found so far but also those which will be foundon the basis of the above mentioned mechanism.

Examples of other drugs for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compounds of formula (I) onatopic dermatitis include steroid drugs, nonsteroidal anti-inflammatorydrugs (NSAID), immunosuppressants prostaglandins, antiallergic drugs;mediator release inhibitors, antihistamines, metabolism-promoters(forskolin preparations, etc.), phosphodiesterase inhibitors, chemokineinhibitors, and the like.

Examples of other drugs for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compounds of formula (I) onallergic conjunctivitis include leukotriene receptor antagonists,antihistamines, mediator release inhibitors, nonsteroidalanti-inflammatory drugs, prostaglandins, steroids, nitric oxide synthaseinhibitor, chemokine inhibitors, and the like.

Examples of other drugs for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compounds of formula (I) onallergic rhinitis include antihistamines, mediator release inhibitors,thromboxane synthase inhibitors, thromboxane A₂ receptor antagonists,leukotriene receptor antagonists, steroids, α adrenaline receptorstimulants, xanthine derivatives, anticholinergic agents,prostaglandins, nitric oxide synthase inhibitors, β₂ adrenaline receptorstimulants, phosphodiesterase inhibitors, chemokine inhibitors, and thelike.

Examples of other drugs for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compounds of formula (I) onasthma include brondilators (β₂ adrenaline receptor stimulants, xanthinederivatives, anticholinergic agents, etc.), antiinflammatants (steroids,nonsteroidal anti-inflammatory drugs (NSAID), etc.), prostaglandins,leukotriene receptor antagonists, phosphodiesterase inhibitors,chemokine inhibitors, oriental drugs, and the like.

Examples of the steroids include, e.g., as drugs for external use,clobetasol propionate, diflorasone acetate, fluocinonide, mometasonefurancarboxylate, betamethasone dipropionate, betamethasone butyratepropionate, betamethasone valerate, difluprednate, budesonide,diflucortolone valerate, amcinonide, halcinonide, dexamethasone,dexamethasone propionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclomethasone propionate, triamcinoloneacetonide, flumethasone pivalate, alclomethasone propionate,clobethasone butyrate, prednisolone, beclomethasone propionate,fludroxycortide, and the like.

Examples of drugs for internal use and injections include cortisoneacetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisonesodium succinate, fludrocortisone acetate, prednisolone, prednisoloneacetate, prednisolone sodium succinate, prednisolone butyl acetate,prednisolone sodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, betamethasone, and thelike.

Examples of inhalations include beclomethasone propionate, fluticasonepropionate, budesonide, flunisolide, triamcinolone, ST-126P,ciclesonide, dexamethasone palomithionate, mometasone furoate,prasterone sulfonate, deflazacort, methylprednisolone sleptanate,methylprednisolone sodium succinate, and the like.

Examples of the nonsteroidal anti-inflammatory drugs include sasapyrine,sodium salicylate, aspirin, aspirin-dialuminate blend, diflunisal,indomethacin, sprofen, ufenamate, dimethylisopropylazulene, bufexamac,felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone,proglumetacin, indometacin famesil, acemetacin, proglumetacin maleate,amfenac sodium, miofezolac, etodolac, ibuprofen; ibuprofen piconol,naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofencalcium, tiaprofen, oxaprozin, pyranoprofen, loxoprofen sodium,alminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate,tolfenamic acid, floctafenine, ketophenylbutazone, oxyfenbutazone,piroxicam, tenoxicam, ampiroxicam, napageln ointment, epirizol,tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpirin,migrenin, saridon, sedes G, amipylo N, sorbon, pilin-based cold drugs,acetaminophen, fenacetine, dimethothiazine mesylate,simetride-containing agents, non-pilin-based cold drugs, and the like.

Examples of the immunosuppressants include protopic (FK-506),methotrexate, cyclosporin, ascomycin, leflunomide, bucillamine,salazosulfapyridine, sirolimus, mycophenolate mofetyl, and the like.

Examples of prostaglandins (hereinafter, abbreviated as PG) include PGreceptor agonists, PG receptor antagonists, and the like.

Examples of PG receptors include PGE receptors (EP1, EP2, EP3 and EP4),PGD receptors (DP, CRTH2), PGF receptors (FP), PGI receptors (IP), TXreceptors (TP), and the like.

Examples of the mediator release inhibitors include tranilast, sodiumcromoglycate, amlexanox, repirinast, ibudilast, tazanolast, pemirolastpotassium and the like.

Examples of the antihistamines include ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate,epinastine hydrochloride, astemizole, ebastine, cetirizinehydrochloride, bepotastine, fexofenadine, loratadine, desloratadine,olopatadine hydrochloride, TAK427, ZCR-2060, NIP-530, mometasonefuroate, mizolastine, BP-294, andolast, auranofin, acrivastine,famotidine, ranitidine, cimetidine, and the like.

Examples of the phosphodiesterase inhibitors include PDE4 inhibitorssuch as roliplam, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633),SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, and the like.

Examples of the leukotriene receptor antagonists include pranlukasthydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757,CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496,BIIL-284, ONO-4057, and the like.

Examples of thromboxane A₂ receptor antagonists include, for Example,seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962, and thelike.

Examples of thromboxane synthase inhibitors include, for Example,ozagrel hydrochloride, imitrodast sodium, and the like.

Examples of xanthine derivatives include, for Example, aminophylline,theophylline, doxophylline, cipamfylline, diprophylline, and the like.

Examples of anticholinergic agents include, for Example, ipratropiumbromide, oxitropium bromide, flutropium bromide, cimetropium bromide,temiverine, tiotropium bromide, revatropate (UK-112166), oxybutininhydrochloride, bethanechol hydrochloride, propiverine hydrochloride,propantheline bromide, methylbenactyzium bromide, butylscopolaminebromide, tolterodine tartrate, trospium chloride, Z-338, UK-112166-04,KRP-197, darifenacin, YM-905, mephenzolate bromide, ipratropium bromide,and the like.

Examples of the β₂ adrenaline receptor stimulants include fenoterolhydrobromide, salbutamol sulfate, terbutaline sulfate, formoterolfumarate, salmeterol xinafoate, isoprotenol sulfate, orciprenalinsulfate, chloroprenaline sulfate, epinephrine, trimetoquinolhydrochloride, hexoprenaline mesyl sulfate, procaterol hydrochloride,tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride,clenbuterol hydrochloride, mabuterol hydrochloride, ritodrinehydrochloride, bambuterol, dopexamine hydrochloride, meradrin tartrate,AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211,AR-C89855, S-1319, and the like.

Examples of the chemokine inhibitors include endogenous ligands ofchemokine receptors or derivatives thereof, and non-peptidic lowmolecular compounds or antibodies for chemokine receptors.

Examples of the endogenous ligands of chemokine receptors includeMIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP4, Eotaxin,MDC, and the like.

Examples of the derivatives of endogenous ligands include AOP-RANTES,Met-SDF-1α, Met-SDF-1β, and the like.

Examples of the antibodies for chemokine receptors include Pro-140, andthe like.

Examples of the non-peptidic low molecular compounds include antagonistsand agonists for CCR1, CCR2, CCR3, CCR4, CCR5, CXCR1, CXCR2, CXCR3 andCXCR4 receptors.

Examples of the oriental drugs include syouseiryuutou, Ephedrae Herbaextracts Liriope platyphylla extracts, and the like.

The compound of the present invention of formula (I) is safe andlow-toxic, thus can be administered to human and mammals other thanhuman (e.g., rat, mouse, rabbit, sheep, swine, bovine, cat, dog, monkey,etc.).

For the purpose above described, the compounds of formula (I),pharmacologically acceptable salts thereof, acid addition salts orhydrates thereof, or a combination of the compounds of formula (I) andother medicaments may be normally administered systemically or locally,usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for Example,ages, body weights, symptoms, the desired therapeutic effects, the routeof administration and the duration of the treatment. For the humanadult, the doses per person are generally from 1 ng to 100 mg, by oraladministration, up to several times per day, and from 0.1 ng to 10 mg,by parenteral administration, up to several times per day, or continuousadministration 1 to 24 hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

To administer the compounds in the present invention of formula (I), useis made of solid preparations for internal use and liquid preparationsfor internal use for oral administration as well as preparations forinjections, external preparations, suppositories, eye drops, nasaldrops, inhalations and the like for parenteral administration.

Examples of the solid preparations for internal use for oraladministration include tablets, pills, capsules, powders, granules andthe like. The capsules include hard capsules and soft capsules.

Such a solid preparation for internal use is prepared by a formulationmethod commonly employed by using one or two or more active substanceseither as it is or as a mixture with an excipient (lactose, mannitol,glucose, microcrystalline cellulose, starch, etc.), a binder(hydroxypropylcellulose, polyvinylpyrrolidone, magnesium metasilicatealuminate, etc.), a disintegrating agent (calcium cellulose glycolate,etc.), a lubricant (magnesium stearate, etc.), a stabilizer and adissolution aid (glutamic acid, aspartic acid, etc.); If necessary, itmay be coated with a coating agent (sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.).It may be coated with two or more layers. Moreover, capsules made of anabsorbable material such as gelatin are involved in the scope thereof.

The liquid preparations for internal use for oral administration includepharmaceutically acceptable aqueous solutions, suspensions, emulsions,syrups, elixirs and the like. Such a liquid preparation is prepared bydissolving, suspending or emulsifying one or more active substances in adiluent commonly employed (purified water, ethanol or a mixture thereof,etc.). Such liquid forms may also further comprise some additives suchas humectants, suspending agents, emulsifying agents, sweetening agents,flavoring agents, aroma, preservatives, buffers and the like.

The dosage forms of the parenteral administration preparations forexternal use include ointments, gels, creams, fomentations, patches,liniments, atomized agents, inhalations, sprays, aerosols, eye drops,nasal drops and the like. Such a preparation contains one or two or moreactive substances and is prepared by a well known method or a commonlyemployed formulation.

Ointments are prepared in accordance with a well known formulation or acommonly employed formulation. For Example, they are prepared bysoftening or melting one or two or more active substances in a base. Theointment base is selected from well known ones or those commonlyemployed. For Example, use may be made of one base or a mixture of twoor more thereof selected from higher fatty acids or higher fatty acidesters (adipic acid, myristic acid, palmitic acid, stearic acid, oleicacid, adipic acid esters, myristic acid esters, palmitic acid esters,stearic acid esters, oleic acid esters, etc.), waxes (beeswax, whalewax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphoricacid esters, etc.), higher alcohols (cetanol, stearyl alcohol,cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.),hydrocarbons (hydrophilic vaseline, white vaseline, refined lanolin,liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol,propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils(castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils(mink oil, yolk oil, squalane, squalene, etc.), water, absorptionpromoters and skin irritation inhibitors. The ointments may furthercontain a humectant, a preservative, a stabilizer, an antioxidant, aflavor, and the like.

Gels are prepared in accordance with a well known formulation or aformulation commonly employed. For Example, they are prepared by meltingone or more active substances in a base. The gel base is selected fromwell known ones or those commonly employed. For Example, use may be madeof one base or a mixture of two or more thereof selected from loweralcohols (ethanol, isopropyl alcohol, etc.), gelling agents(carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,ethylcellulose, etc.), neutralizing agents (triethanolamine,diisopropanolamine, etc.), surfactants (polyethylene glycolmonostearate, etc.), gums, water, absorption promoters and skinirritation inhibitors. The gels may further contain a preservative, anantioxidant, a flavor, and the like.

Creams are prepared in accordance with a well known formulation or aformulation commonly employed. For Example, they are prepared by meltingor emulsifying one or more active substances in a base. The cream baseis selected from well known ones or those commonly employed. ForExample, use may be made of one base or a mixture of two or more thereofselected from higher fatty acid esters, lower alcohols, hydrocarbons,polyhydric alcohols (propylene glycol, 1,3-butylene:glycol, etc.),higher alcohols-(2-hexyldecanol, cetanol, etc.), emulsifiers(polyoxyethylene alkyl ethers, fatty acid esters, etc.), water,absorption promoters and skin irritation inhibitors. The creams mayfurther contain a preservative, an antioxidant, a flavor, and the like.

Fomentations are prepared in accordance with a well known formulation ora formulation commonly employed. For Example, they are prepared bymelting one or more active substances in a base, kneading and thenapplying and spreading the kneaded matter on a substrate. Thefomentation base is selected from well known ones or those commonlyemployed. For Example, use may be made of one base or a mixture of twoor more thereof selected from thickeners (polyacrylic acid,polyvinylpyrrolidone, gum acacia, starch, gelatin, methylcellulose,etc.), moistening agents (urea, glycerin, propylene glycol, etc.),fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.), water,dissolution aids, tackifiers and skin irritation inhibitors. Thefomentations may further contain a preservative, an antioxidant, aflavor, and the like.

Patches are prepared in accordance with a well known formulation or aformulation commonly employed. For Example, they are prepared by meltingone or more active substances in a base and then applying and spreadingon a substrate. The patch base is selected from well known ones or thosecommonly employed. For Example, use may be made of one base or a mixtureof two or more thereof selected from polymer bases, fats and oils,higher fatty acids, tackifiers and skin irritation inhibitors. Thepatches may further contain a preservative, an antioxidant, a flavor,and the like.

Liniments are prepared in accordance with a well known formulation or aformulation commonly employed. For Example, they are prepared bydissolving, suspending or emulsifying one or two or more activesubstances in one or more media selected from water, alcohols (ethanol,polyethylene glycol, etc.), higher fatty acids, glycerin, soap,emulsifiers, suspending agents, and the like. The liniments may furthercontain a preservative, an antioxidant, a flavor, and the like.

Atomized agents, inhalations and sprays may contain, in addition to adiluent commonly employed, a stabilizer such as sodium hydrogen sulfite,a buffering agent for imparting isotonicity, for Example, an isotonicagent such as sodium chloride, sodium citrate or citric acid. Methodsfor producing a spray are described in detail in, for Example, U.S. Pat.No. 2,868,691 and U.S. Pat. No. 3,095,355.

The injections for parenteral administration include all forms ofinjections and also drops, for Example, an intramuscular injection, asubcutaneous injection, an intradermal injection, an intraarterialinjection, an intravenous injection, a peritoneal injection, anintrathecal injection, an intravenous drop, and the like.

The injections for parenteral administration include solutions,suspensions, emulsions and solid injections to be dissolved or suspendedbefore use. Such an injection is used by dissolving, suspending oremulsifying one or more active substances in a solvent. The solventincludes, for Example, distilled water for injection, physiologicalsaline, vegetable oils, alcohols such as propylene glycol, polyethyleneglycol and ethanol, and mixtures thereof. The injection may furthercontain a stabilizer, a dissolution aid (glutamic acid, aspartic acid,Polysorbate 80 (registered trademark), etc.), a suspending agent, anemulsifier, a soothing agent, a buffer, a preservative, and the like.Such an injection may be produced by sterilizing at the final step oremploying an aseptic process. Alternatively, it is also possible that anaseptic solid product such as a freeze-dried product is produced andsterilized or dissolved in aseptic distilled water for injection oranother solvent before use.

Eye drops for parenteral administration may be in the form of liquid,suspension, emulsion, liquid dissolved in a solvent in use or ointment.

These eye drops are prepared by any known method. For Example, one ormore active substances are dissolved, suspended or emulsified in asolvent. As such a solvent for eye drops, there may be used sterilizedpurified water, physiological saline and other aqueous solvents ornon-aqueous solvents for injection (e.g., vegetable oils, etc.), singlyor in combination thereof. The eye drops may contain ones selected froman isotonic agent (e.g., sodium chloride, concentrated glycerin, etc.),a buffering agent (e.g., sodium phosphate, sodium acetate, etc.), asurfactant (e.g., Polysolvate 80 (trade name), Polyoxyl stearate 40,polyoxyethylene-hydrogenated castor oil, etc.), a stabilizer (sodiumcitrate, sodium edetate, etc.), a preservative (e.g., benzalconiumchloride, paraben, etc.), and the like. The eye drops are sterilized atthe final step or prepared by an aseptic process. Alternatively, anaseptic solid agent such as freeze-dried product which has previouslybeen prepared may be rendered aseptic or dissolved in aseptic distilledwater for injection or other solvent before use.

The inhalations for parenteral administration include aerosols, powdersfor inhalation and liquids for inhalation. Such inhalations may bedissolved or suspended in water or another adequate medium for use.

The inhalations may be prepared in accordance with a well known method.

For Example, liquid preparations for inhalation may be, if necessary,prepared by appropriately selecting a preservative (benzalkoniumchloride, paraben, etc.), a colorant, a buffering agent (sodiumphosphate, sodium acetate, etc.), an isotonic agent (sodium chloride,concentrated glycerin, etc.), a thickener (carboxyvinyl polymer, etc.),an absorption promoter, and the like.

Powders for inhalation may be prepared, if necessary, by appropriatelyselecting a lubricant (stearic acid and its salt, etc.), a binder(starch, dextrin, etc.), an excipient (lactose, cellulose, etc.), acolorant, a preservative (benzalkonium chloride, paraben, etc.), anabsorption promoter, and the like.

When the liquids for inhalation are administered, a sprayer (atomizer,nebulizer) is usually used. When the powders for inhalation are used, aninhalation administration apparatus for powder agents is usually used.

Other compositions for parenteral administration include suppositoriesand pessaries for vaginal administration which contain one or moreactive substances, and are prepared in accordance with commonformulations.

The compounds of the present invention are designated as follows.

The name of the compounds used in the present specification isdesignated according to IUPAC regulations, or using a computer programconducting designation generally according to IUPAC regulations,ACD/Name (registered trademark, version 6.00, Advanced ChemistryDevelopment Inc.).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on ReferenceExamples and Examples, but the present invention is not limited thereto.

The solvents in the parentheses show the eluting or developing solventsin chromatographic separations or TLC and the ratios of the solventsused are by volume.

The solvents in the parentheses in NMR show the solvents formeasurement.

MS was conducted to detect only positive ions (Pos., 20 V) using an ESImethod (an electron spray ionization method) unless otherwise stated.

Measurement conditions for HPLC was conducted as follows unlessotherwise stated.

Column used: Xterra (registered trademark) MS C₁₈ 5 μm, 4.6×50 mm I.D.

Flow rate used: 3 ml/min

Solvents used

Liquid A: an aqueous solution of 0.1% trifluoroacetic acid

Liquid B: a solution of 0.1% trifluoroacetic acid-acetonitrile

After initiating the measurement, for 0.5 minutes, the mixing ratio ofLiquid A and Liquid B was fixed at 95/5. Thereafter, for 2.5 minutes,the mixing ratio of Liquid A and Liquid B was changed linearly to 0/100.Then, for 0.5 minute, the mixing ratio of Liquid A and Liquid B wasfixed at 0/100. Then, for 0.01 minutes, the mixing ratio of Liquid A andLiquid B was changed linearly to 95/5.

REFERENCE EXAMPLE 1 2,6-dibromo-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of 2,6-dibromo-3-aminopyrazine (2.53 g) in1,2-dimethoxyethane (20 mL), 60% sodium hydride (1 g) was added undercooling with ice. The mixture was stirred for 30 minutes at roomtemperature. To the mixture, p-toluenesulfonyl chloride (1.91 g) wasadded under cooling with ice. The mixture was stirred for 1.5 hours at0° C. 2N hydrochloric acid was added to the reaction mixture, and themixture was concentrated. The aqueous layer was extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=5:1→21) to give the title compound(2.04 g) having the following physical data.

TLC: Rf 0.28(hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 8.44(s, 1H), 7.86(d, J=8.1 Hz, 2H), 7.38(d, J=8.1 Hz,2H), 2.37(s, 3H).

EXAMPLE 16-bromo-2-(phenylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of benzyl alcohol (0.153 mL) in 1,4-dioxane (3 mL), 60%sodium hydride (118 mg) was added at room temperature. The mixture wasstirred for 30 minutes, and the compound prepared in Reference Example 1(300 mg) was added to the mixture. The mixture was stirred for 1.5 hoursat 65° C. 1N hydrochloric acid was added to the reaction mixture, andthe mixture was concentrated. The aqueous layer was extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=6:1) to give the title compound (305mg) having the following physical data.

TLC: Rf 0.57(hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 11.12(s, 1H), 7.92(s, 1H), 7.85(dd, J=6.6, 1.8 Hz, 2H),7.52(dd, J=6.6, 1.8 Hz, 2H), 7.43-7.34(m, 5H), 5.36(s, 2H), 2.35(s, 3H).

Example 1(1)-1(8)

The following compounds were obtained, using the compound prepared inReference Example 1 and a corresponding alcohol compound in stead ofbenzyl alcohol, by the same procedure as Example 1.

Example 1(1)6-bromo-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.59(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.15(br, 1H), 8.77(d, J=1.8 Hz, 1H), 8.57(dd, J=5.1,1.8 Hz, 1H), 7.97-7.94(m, 2H), 7.84(d, J=8.1 Hz, 2H), 7.45(dd, J=7.8,4.8 Hz, 1H), 7.36(d, J=8.1 Hz, 2H), 5.39(s, 2H), 2.35(s, 3H).

Example 1(2)6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.47(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.06(br, 1H), 7.91(s, 1H), 7.84(d, J=8.4 Hz, 2H),7.35(d, J=8.4 Hz, 2H), 7.15(d, J=1.8 Hz, 1H), 7.04(dd, J=8.1, 1.8 Hz,1H), 6.95(d, J=8.1 Hz, 1H), 5.28(s, 2H), 3.76(s, 3H), 3.75(s, 3H),2.35(s, 3H).

Example 1(3)6-bromo-2-((3-(2-dimethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.32(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.67(d, J=8.1 Hz, 2H), 7.47(s, 1H), 7.19(d, J=1-0.8 Hz,1H), 7.16(d, J=8.1 Hz, 2H), 7.09(dd, J=8;1, 1.8 Hz, 1H), 7.01(d, J=8.1Hz, 1H), 5.13(s, 2H), 4.22(t, J=5.4 Hz, 2H), 3.77(s, 3H), 3.24(t, J=5.4Hz, 2H), 2.69(s, 6H), 2.29(s, 3H).

Example 1(4)6-bromo-2-((3-(2-(morpholin-4-yl)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.55(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.80(m, 3H), 7.31(d, J=8.4 Hz, 2H), 7.18(d, J=1.8 Hz,1H), 7.05(dd, J=8.1, 1.8 Hz, 1H), 6.97(d, J=8.1 Hz, 1H), 5.24(s, 2H),4.11(t, J=5.1 Hz, 2H), 3.76(s, 3H), 3.59(m, 4H), 2.82(t, J=5.1 Hz, 2H),2.61(m, 4H), 2.34(s, 3H).

Example 1(5)6-bromo-2-((3-(2-diethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.33(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.67(d, J=7.5 Hz, 2H), 7.47(s, 1H), 7.19(brs, 1H),7.16(d, J=7.5 Hz, 2H), 7.09(brd, J=7.2 Hz, 1H), 7.01(d, J=7.2 Hz, 1H),5.14(s, 2H), 4.25(t, J=5.1 Hz, 2H), 3.78(s, 3H), 3.38(m, 2H), 3.12(q,J=7.2 Hz, 4H), 2.29(s, 3H), 1.18(t, J=7.2 Hz, 6H).

Example 1(6)6-bromo-2-((3-(2-diisopropylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.43(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.68(d, J=8.1 Hz, 2H), 7.51(br, 1H), 7.19-7.15(m, 3H),7.05(d, J=8.1 Hz, 111), 6.98(d, J=8.1 Hz, 1H), 5.16(s, 2H), 4.12(m, 2H),3.76(s, 3H), 3.60-3.30(m, 4H), 2.29(s, 3H), 1.21(m, 12H).

Example 1(7)6-bromo-2-((3-(2-(N-methyl-N-(2-dimethylaminoethyl)amino)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazinetriethylamine salt

TLC: Rf 0.45(chloroform:methanol:triethylamine=9:1:0.5);

NMR(d₆-DMSO): δ 7.63(d, J=7.8 Hz, 2H), 7.36(s, 1H), 7.12(m, 3H), 7.01(d,J=7.8 Hz, 1H), 6.95(d, J=7.8 Hz, 1H), 5.10(s, 2H), 4.09(t, J=5.4 Hz,2H), 3.75(s, 3H), 2.95(m, 8H), 2.80(t, J=5.4 Hz, 2H), 2.70(t, J=6.0 Hz,2H), 2.59(s, 6H), 2.31(s, 3H), 2.27(s, 3H), 1.12(t, J=7.5 Hz, 9H).

Example 1(8)6-bromo-2-((3-dimethylaminomethyl-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.17(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.73(d, J=7.8 Hz, 2H), 7.65(s, 1H), 7.59(dd, J=8.7, 1.8Hz, 1H), 7.53(d, J=1.8 Hz, 1H), 7.24(d, J=7.8 Hz, 2H), 7.15(d, J=8.7 Hz,1H), 5.23(s, 2H), 4.18(s, 2H), 3.85(s, 3H), 2.69(s, 6H), 2.31(s, 3H).

EXAMPLE 25,6-dimethyl-2-((3-(2-dimethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using 2-bromo-3-amino-5,6-dimethylpyrazine in stead of2,6-dibromo-3-aminopyrazine, and3-(2-dimethylaminoethyl)oxy-4-methoxybenzyl alcohol in stead of benzylalcohol, by the same procedure as a series of reactions of ReferenceExample 1→Example 1.

TLC: Rf 0.30(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.85(d, J=8.4 Hz, 2H), 7.31(d, J=8.4 Hz, 2H), 7.13(d,J=2.1 Hz, 1H), 7.02(dd, J=8.4, 2.1 Hz, 1H), 6.93(d, J=8.4 Hz, 1H),5.21(s, 2H), 4.05(t, J=6.0 Hz, 2H), 3.74(s, 3H), 2.72(t, J=6.0 Hz, 2H),2.34(s, 3H), 2.29(s, 6H), 2.24(s, 3H), 2.18(s, 3H).

Example 2(1)-2(5)

The following compounds were obtained, using a corresponding pyrazinecompound in stead of 2-bromo-3-amino-5,6-dimethylpyrazien and acorresponding alcohol compound in stead of3-(2-dimethylaminoethyl)oxy-4-methoxybenzyl alcohol, by the sameprocedure as Example 2.

Example 2(1)6-methyl-2-((3-(2-(morpholin-4-yl)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.58(chloroform:methanol=10:1);

NMR (CD₃OD): δ 7.85(d, J=8.4 Hz, 2H), 7.52(s, 1H), 7.27(d, J=8.4 Hz,2H), 7.13(d, J=1.8 Hz, 1H), 7.00(dd, J=8.1, 1.8 Hz, 1H), 6.92(d, J=8.1Hz, 1H), 5.33(s, 2H), 4.16(t, J=5.7 Hz, 2H), 3.82(s, 3H), 3.69(m, 4H),2.81(t, J=5.7 Hz, 2H), 2.62(m, 4H), 2.37(s, 3H), 2.29(s, 3H).

Example 2(2) 6-methyl-2-((3(2-diethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.33(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.78(d, J=8.1 Hz, 2H), 7.50(s, 1H), 7.28(d, J=8.1 Hz,2H), 7.15(s, 1H), 7.04(d, J=8.1 Hz, 1H), 6.95(d, J=8.1, Hz, 1H), 5.23(s,2H), 4.05(t, J=6.0 Hz, 2H), 3.75(s, 3H), 2.93(t, J=6.0 Hz, 2H), 2.69(q,J=7.2 Hz, 4H), 2.33(s, 3H), 2.23(s, 3H), 1.01(t, J=7.2 Hz, 6H).

Example 2(3)6-methyl-2-((3-(2-diisopropylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.43(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.79(d, J=8.1 Hz, 2H), 7.53(s, 1H), 7.29(d, J=8.1 Hz,2H), 7.12(s, 1H), 7.02(d, J=8.1 Hz, 1H), 6.93(d, J=8.1 Hz, 1H), 5.24(s,2H), 3.89(t, J=6.9 Hz, 2H), 3.74(s, 3H), 3.08(m, 2H), 2.86(t, J=6.9 Hz,2H), 2.33(s, 3H), 2.24(s, 3H), 1.00(d, J=6.3 Hz, 12H).

Example 2(4)6-methyl-2-((3-(2-(N-methyl-N-(2-dimethylaminoethyl)amino)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazinetriethylamine salt

TLC: Rf 0.45(chloroform:methanol:triethylamine=9:1:0.5),

NMR(d₆-DMSO): δ 7.75(d, J=8.1 Hz, 2H), 7.43(s, 4H), 7.24(d, J=8.1 Hz,2H) 7:15(s, 1H), 7.03(d, J=8.1 Hz, 1H), 6.95(d, J=8.1 Hz, 1H), 5.21(s,2H), 4.08(t, J=5.1 Hz, 2H), 3.75(s, 3H), 2.96(q, J=7.2 Hz, 6H), 2.88(t,J=6.0 Hz, 2H), 2.79(t, J=5.1 Hz, 2H), 2.68(t, J=6.0 Hz, 2H), 2.54(s,6H), 2.31(s, 3H), 2.30(s, 3H), 2.20(s, 3H), 1.13(t, J=7.2 Hz, 9H).

Example 2(5)6-methyl-2-((3-dimethylaminomethyl-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.17(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.79(d, J=8.4 Hz, 2H), 7.53(s, 1H), 7.46(m, 2H), 7.30(d,J=8.4 Hz, 2H), 7.04(d, J=9.0 Hz, 1H), 5.27(s, 2H), 3.80(s, 3H), 3.71(s,2H), 2.37(s, 6H), 2.33(s, 3H), 2.24(s, 3H).

REFERENCE EXAMPLE 2 2-chloro-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of 2,3-dichloropyrazine (5 g) and4-methylbenzenesulfonamide (5.74 g) in dimethylsulfoxide (60 mL),potassium carbonate (13.91 g) was added. The mixture was stirred for 4hours at 110° C. The reaction mixture was cooled to room temperature,and water and 2N hydrochloric acid were added to the mixture. Theprecipitated sold was collected by filtration, and dried to give thetitle compound (7.67 g) having the following physical data.

TLC: Rf 0.74(chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 11.19(br, 10H), 8.22(d, J=2.4 Hz, 1H), 8.11(d, J=2.4Hz, 1H), 7.88(d, J=8.4 Hz, 2H), 7.38(d, J=8.4 Hz, 2H), 2.37(s, 3H).

EXAMPLE 3 2-(phenylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using the compound prepared in Reference Example 2 in stead of thecompound prepared in Reference Example 1, by the same procedure as aseries of reactions of Example 1.

TLC: Rf 0.38(hexane:ethyl acetate=2:1);

NMR (d₆-DMSO): δ 10.91(brs, 1H), 7.87(d, J=8.1 Hz, 2H), 7.73(m, 2H),7.50(m, 2H), 7.36(m, 5H), 5.38(s, 2H), 2.35(s, 3H).

Example 3(1)-3(11)

The following compounds were obtained, using the compound prepared inReference Example 2 and a corresponding alcohol compound in stead ofbenzyl alcohol, by the same procedure as a series of reactions ofExample 3.

Example 3(1)2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.43(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 10.95(s, 1H), 8.74(d, J=1.8 Hz, 1H), 8.54(dd, J=4.8, 1.8Hz, 1H), 7.92(d, J=7.8 Hz, 1H), 7.85(d, J=8.4 Hz, 2H), 7.75(d, 3.0 Hz,1H), 7.73(d, J=3.0 Hz, 1H), 7.41(dd, J=7.8, 4.8 Hz, 1H), 7.35(d, J=8.4Hz, 2H), 5.40(s, 2H), 2.34(s, 3H).

Example 3(2)2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.62(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.88(s, 1H), 7.86(d, J=8.4 Hz, 2H), 7.71(m, 2H),7.34(d, J=8.4 Hz, 2H), 7.29(dd, J=7.8, 7.2 Hz, 2H), 6.97(d, J=7.8 Hz,2H), 6.94(t, J=7.2 Hz, 1H), 4.60(m, 2H), 4.34(m, 2H), 2.34(s, 3H).

Example 3(3)2-((pyridin-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.35(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.04(s, 1H), 8.56(d, J=5.7 Hz, 2H), 7.88(d, J=8.4 Hz,2H), 7.74(d, J=2.7 Hz, 1H), 7.72(d, J=2.7 Hz, 1H), 7.49(d, J=5.7 Hz,2H), 7.36(d, J=8.4 Hz, 2H), 5.43(s, 2H), 2.35(s, 3H).

Example 3(4)2-((3-methoxymethyloxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.67(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.91(s, 1H), 7.86(d, J=8.4 Hz, 2H), 7.82-7.64(m, 2H),7.35(d, J=8.4 Hz, 2H), 7.29(t, J=7.8 Hz, 1H), 7.17(brs, 1H), 7.11(brd,J=7.8 Hz, 1H), 6.98(m, 1H), 5.34(s, 2H), 5.10(s, 2H), 3.36(s, 3H),2.34(s, 3H).

Example 3(5)2-(3-aminophenylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.56(benzene:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 7.88(d, J=8.1 Hz, 2H), 7.74(d, J=3.0 Hz, 1H), 7.71(d,J=3.0 Hz, 1H), 7.36(d, J=8.1 Hz, 2H), 7.01(t, J=7.2 Hz, 1H),6.63-6.61(m, 2H), 6.57(d, J=7.2 Hz, 1H), 5.24(s, 2H), 2.36(s, 3H).

Example 3(6)2-((3-(2-dimethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.27(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.78(d, J=8.4 Hz, 2H), 7.54(d, J=3.0 Hz, 1H), 7.49(d,J=3.0 Hz, 1H), 7.26(d, J=8.4 Hz, 2H), 7.14(d, J=1.5 Hz, 1H), 7.04(dd,J=8.4, 1.5 Hz, 1H), 6.96(d, J=8.4 Hz, 1H), 5.23(s, 2H), 4.11(t, J=5.4Hz, 2H), 3.75(s, 3H), 2.91(t, J=5.4 Hz, 2H), 2.43(s, 6H), 2.32(s, 3H).

Example 3(7)2-((3-(2-(morpholin-4-yl)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.54(chloroform:methanol=10:1);

NMR (CD₃OD): δ 7.99(d, J=7.8 Hz, 2H), 7.64(d, J=3.0 Hz, 1H), 7.62(d,J=3.0 Hz, 1H), 7.29(d, J=7.8 Hz, 2H), 7.14(d, J=2.1 Hz, 1H), 7.02(dd,J=8.4, 2.1 Hz, 1H), 6.93(d, J=8.4 Hz, 1H), 5.35(s, 2H), 4.16(t, J=5.4Hz, 2H), 3.82(s, 3H), 3.70(m, 4H), 2.82(t, J=5.4 Hz, 2H), 2.64(m, 4H),2.38(s, 3H).

Example 3(8)2-((3-(2-diethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.33(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.78(d, J=8.1 Hz, 2H), 7.53(d, J=2.7 Hz, 1H), 7.47(d,J=2.7 Hz, 1H), 7.25(d, J=8.1 Hz, 2H), 7.14(d, J=1.2 Hz, 1H), 7.04(dd,J=8.1, 1.2 Hz, 1H), 6.96(d, J=8.1 Hz, 1H), 5.23(s, 2H), 4.12(t, J=6.0Hz, 2H), 3.75(s, 3H), 3.08(t, J=6.0 Hz, 2H), 2.84(q, J=6.9 Hz, 4H),2.32(s, 3H), 1.07(t, J=6.9 Hz, 6H).

Example 3(9)2-((3-(2-diisopropylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.43(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.81(d, J=8.1 Hz, 2H), 7.60(m, 2H), 7.29(d, J=8.1 Hz,2H), 7.12(d, J=1.5 Hz, 1H), 7.03(dd, J=8.1, 1.5 Hz, 1H), 6.95(d, J=8.1Hz, 1H), 5.26(s, 2H), 3.98(m, 2H), 3.75(s, 3H), 3.36(m, 2H), 3.03(br,2H), 2.33(s, 3H), 1.08(d, J=7.2 Hz, 12H).

Example 3(10)2-((3-(2-(N-methyl-N-(2-dimethylaminoethyl)amino)ethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazinetriethylamine salt

TLC: Rf 0.45(chloroform:methanol:triethylamine=9:1:0.5);

NMR(d₆-DMSO): δ 7.71(d, J=7.8 Hz, 2H), 7.39(d, J=2.7 Hz, 1H), 7.25(d,J=2.7 Hz, 1H), 7.18(d, J=7.8 Hz, 2H), 7.12(s, 1H), 7.00(d, J=8.1 Hz,1H), 6.97(d, J=8.1 Hz, 1H), 5.18(s, 2H), 4.08(t, J=5.7 Hz, 2H), 3.74(s,3H), 2.97(m, 8H), 2.79(t, J=5.4 Hz, 2H), 2.71(t, J=5.7 Hz, 2H), 2.60(s,6H), 2.31(s, 3H), 2.29(s, 3H), 1.14(t, J=7.2 Hz, 9H).

Example 3(11)2-((3-dimethylaminomethyl-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.17(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.79(d, J=7.8 Hz, 2H), 7.55(d, J=2.7 Hz, 1H), 7.51(d,J=2.7 Hz, 1H), 7.47(s, 2H), 7.26(d, J=7.8 Hz, 2H), 7.06(d, J=9.3 Hz,1H), 5.26(s, 2H), 3.85(s, 2H), 3.81(s, 3H), 2.46(s, 6H), 2.32(s, 3H).

EXAMPLE 42-((pyridin-3-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

The title compounds having the following physical data was obtained,using 4-chlorobenzenesulfonamide in stead of 4-methylbenzenesulfonamide,and 3-(hydroxymethyl)pyridine in stead of benzyl alcohol, by the sameprocedure as a series of reactions of Reference Example 2→Example 1.

TLC: Rf 0.40(hexane:ethyl acetate=3:7);

NMR(d₆-DMSO): δ 11.17(s, 1H), 8.74(d, J=1.8 Hz, 1H), 8.54(dd, J=4.8, 1.8Hz, 1H), 7.97(d, J=8.4 Hz, 2H), 7.92(d, J=8.1 Hz, 1H), 7.79(d, J=3.0 Hz,1H), 7.74(d, J=3.0 Hz, 1H), 7.64(d, J=8.4 Hz, 2H), 7.42(dd, J=8.1, 4.8Hz, 1H), 5.41(s, 2H).

Example 4(1)-4(5)

The compounds having the following physical data were obtained, using acorresponding sulfonamide compound in stead of4-chlorobenzenesulfonamide, and a corresponding alcohol compound instead of 3-(hydroxymethyl)pyridine, by the same procedure as a series ofreactions of Example 4.

Example 4(1)2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

TLC: Rf 0.68(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.11(s, 1H), 7.97(d, J=8.4 Hz, 2H), 7.76(m, 1H),7.72(m, 1H), 7.63(d, J=8.4 Hz, 2H), 7.29(dd, J=8.1, 7.2 Hz, 2H), 6.97(d,J=8.1 Hz, 2H), 6.94(t, J=7.2 Hz, 1H), 4.61(m, 2H), 4.34(m, 2H).

Example 4(2)2-((pyridin-3-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

TLC: Rf 0.21(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.11(s, 1H), 8.75(d, J=2.1 Hz, 1H), 8.55(dd, J=4.5, 2.1Hz, 1H), 8.05(dd, J=7.2, 5.1 Hz, 2H), 7.93(m, 1H), 7.79(d, J=3.0 Hz,1H), 7.75(d, J=3.0 Hz, 1H), 7.50-7.35(m, 3H), 5.42(s, 2H).

Example 4(3)2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

TLC: Rf 0.33(hexane:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.04(s, 1H), 8.04(m, 2H), 7.75(m, 1H), 7.72(m, 1H),7.39(t, J=8.7 Hz, 2H), 7.29(t, J=8.7 Hz, 2H), 6.97(d, J=7.5 Hz, 2H),6.92(d, J=7.2 Hz, 1H), 4.61(m, 2H), 4.34(m, 2H).

Example 4(4)2-((pyridin-3-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

TLC: Rf 0.40(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 10.95(s, 1H), 8.74(d, J=1.8 Hz, 1H), 8.54(dd, J=4.8, 1.8Hz, 1H), 7.93(dt, J=8.1, 1.8 Hz, 1H), 7.89(d, J=8.4 Hz, 2H), 7.76(d,J=3.0 Hz, 1H), 7.74(d, J=3.0 Hz, 1H), 7.42(dd, J=8.1, 4.8 Hz, 1H),7.38(d, J=8.4 Hz, 2H), 5.40(s, 2H), 2.65(q, J=7.5 Hz, 2H), 1.16(t, J=7.5Hz, 3H).

Example 4(5)2-(phenylmethyloxy)-3-(2-methoxy-4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.59(hexane:ethyl acetate=1:1);

NMR(CDCl₃): δ 7.98(d, J=8.1 Hz, 1H), 7.96(s, 1H), 7.68(d, J=3.0 Hz, 1H),7.63(d, J=3.0 Hz, 1H), 7.44-7.40(m, 5H), 6.86(d, J=8.1 Hz, 1H), 6.66(s,1H), 5.40(s, 2H), 3.72(s, 3H), 2.36(s, 3H).

EXAMPLE 52-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

The title compound having the following physical data was obtained,using 2,3-dichloroquinoxaline in stead of 2,3-dichloropyrazine, and3-(hydroxymethyl)pyridine in stead of benzyl alcohol, by the sameprocedure as a series of reactions of Reference Example 2→Example 1.

TLC: Rf 0.22(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.39(brs, 1H), 8.84(d, J=1.8 Hz, 1H), 8.58(dd, J=4.5,1.8 Hz, 1H), 8.06(d, J=8.1 Hz, 2H), 8.02(m, 1H), 7.80-7.65(m, 2H),7.58-7.50(m, 2H), 7.46(m, 1H), 7.40(d, J=8.1 Hz, 2H), 5.57(s, 2H),2.35(s, 3H).

Example 5(1)-5(17)

The following compounds were obtained, using 2,3-dichloroquinoxalinecompound or a corresponding pyrazine compound, a correspondingsulfonamide compound in stead of 4-methylbenzenesulfonamide, and3-(hydroxymethyl)pyridine in stead of benzyl alcohol, by the sameprocedure as a series of reactions of Example 5.

Example 5(1)2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

TLC: Rf 0.71(hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 11.30(br, 1H), 8.05(m, 2H), 7.70(m, 2H), 7.50(m, 2H),7.40-7.28(m, 4H), 7.01-6.95(m, 3H), 4.75(m, 2H), 4.43(m, 2H), 2.33(s,3H).

Example 5(2)2-((pyridin-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

TLC: Rf 0.51(chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 11.46(br, 1H), 8.60(m, 2H), 8.06(m, 2H), 7.73(m, 1H),7.65(m, 1H), 7.59(m, 2H), 7.52(m, 2H), 7.40(m, 2H), 5.59(s, 2H), 2.34(s,3H).

Example 5(3)2-((pyridin-3-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

TLC: Rf 0.15(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 12.00-11.00(br, 1H), 8.82(d, J=1.8 Hz, 1H), 8.56(dd,J=4.8, 1.8 Hz, 1H), 8.14(d, J=8.4 Hz, 2H), 8.01(dt, J=6.0, 1.8 Hz, 1H),7.72(m, 2H), 7.67(d, J=8.4 Hz, 2H), 7.53(m, 2H), 7.44(m, 1H), 5.55(s,2H).

Example 5(4)2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

TLC: Rf 0.83(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.50(brs, 1H), 8.20-8.10(m, 2H), 7.80-7.70 (m, 2H),7.67(d, J=7.8 Hz, 2H), 7.52(m, 2H), 7.29(t, J=7.8 Hz, 2H), 6.99(d, J=7.8Hz, 2H), 6.94(t, J=7.2 Hz, 1H), 4.75(m, 2H), 4.42(m, 2H).

Example 5(5)2-((pyridin-4-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

TLC: Rf 0.12(chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 8.58(m, 2H), 8.13(d, J=8.4 Hz, 2H), 7.70-7.57 (m, 4H),7.55(d, J=5.7 Hz, 2H), 7.45(m, 2H), 5.55(s, 2H).

Example 5(6)2-((pyridin-3-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

TLC: Rf 0.15(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.50(brs, 1H), 8.82(d, J=1.8 Hz, 1H), 8.56 (dd, J=4.5,1.8 Hz, 1H), 8.21(m, 2H), 8.01(dt, J=7.8, 1.8 Hz, 1H), 7.78-7.66(m, 2H),7.52(m, 2H), 7.45(m, 1H), 7.41(m, 2H), 5.55(s, 2H).

Example 5(7)2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

TLC: Rf 0.71(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.41(brs, 1H), 8.22(m, 2H), 7.73(m, 1H), 7.67(m, 1H),7.52(m, 2H), 7.43(t, J=8.7 Hz, 2H), 7.30(dd, J=8.7, 7.5 Hz, 2H), 7.00(d,J=7.8 Hz, 2H), 6.94(t, J=7.5 Hz, 1H), 4.75(m, 2H), 4.42(m, 2H).

Example 5(8)2-((pyridin-4-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

TLC: Rf 0.10(chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 8.59(m, 2H), 8.24(m, 2H), 7.75(m, 1H), 7.65(m, 1H),7.58(m, 2H), 7.51(m, 2H), 7.44(m, 2H), 5.57(s, 2H).

Example 5(9)2-((pyridin-3-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

TLC: Rf 0.18(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.40(brs, 1H), 8.82(d, J=1.5 Hz, 1H), 8.56(dd, J=4.8,1.5 Hz, 1H), 8.06(d, J=8.4 Hz, 2H), 8.01(m, 1H), 7.80-7.65(m, 2H),7.60-7.48(m, 2H), 7.44(m, 1H), 7.42(d, J=8.4 Hz, 2H), 5.55(s, 2H),2.63(q, J=7.2 Hz, 2H), 1.14(t, J=7.2 Hz, 3H).

Example 5(10)2-(2-phenoxyethyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

TLC: Rf 0.76(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.28(s, 1H), 8.07(d, J=8.4 Hz, 2H), 7.71(m, 1H),7.66(m, 1H), 7.51(m, 2H), 7.41(d, J=8.4 Hz, 2H), 7.30(dd, J=8.1, 7.2 Hz,2H), 6.99(d, J=8.1 Hz, 2H), 6.94(t, J=7.2 Hz, 1H), 4.74(m, 2H), 4.42(m,2H), 2.63(q, J=7.5 Hz, 2H), 1.14(t, J=7.5 Hz, 3H).

Example 5(11)2-((pyridin-4-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

TLC: Rf 0.10(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 8.59(m, 2H), 8.08(d, J=8.1 Hz, 2H), 7.74(m, 1H), 7.65(m,1H), 7.59(d, J=5.7 Hz, 2H), 7.51(m, 2H), 7.43(d, J=8.1 Hz, 2H), 5.58(s,2H), 2.64(q, J=7.5 Hz, 2H), 1.15(t, J=7.5 Hz, 3H).

Example 5(12)2-(phenylmethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

TLC: Rf 0.71(hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 11.27(s, 1H), 8.04(d, J=7.8 Hz, 2H), 7.68(m, 2H),7.58(d, J=6.9 Hz, 2H), 7.51(m, 2H), 7.44-7.28(m, 5H), 5.52(s, 2H),2.33(s, 3H).

Example 5(13)2-((pyridin-3-yl)methyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

TLC: Rf 0.49(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.36(brs, 1H), 8.83(d, J=1.5 Hz, 1H), 8.56(dd, J=4.5,1.5 Hz, 1H), 8.06(d, J=8.4 Hz, 2H), 8.01(d, J=4.5 Hz, 1H), 7.69(m, 2H),7.52(m, 2H), 7.44(m, 1H), 7.40(d, J=8.4 Hz, 2H), 5.55(s, 2H), 2.59(t,J=7.5 Hz, 2H), 1.55(q, J=7.5 Hz, 2H), 0.84(t, J=7.5 Hz, 3H).

Example 5(14)6-phenyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.30(hexane:ethyl acetate=1:2);

NMR(d₆-DMSO): δ 11.05(brs, 1H), 8.82(d, J=2.1 Hz, 1H), 8.54(dd, J=3.9,2.1 Hz, 1H), 8.37(s, 1H), 7.99(dd, J=3.9, 1.8 Hz, 3H), 7.89(d, J=8.1 Hz,211), 7.45-7.36(m, 6H), 5.56(s, 2H), 2.35(s, 3H).

Example 5(15)5-phenyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.29(hexane:ethyl acetate=1:2);

NMR (d₆-DMSO): δ 11.14(brs, 1H), 8.79(m, 1H), 8.55(m, 1H), 8.35(s, 1H),7.96(m, 4H), 7.77(d, J=6.9 Hz, 2H), 7.46-7.36(m, 5H), 5.47(s, 2H),2.33(s, 3H).

Example 5(16)5-phenyl-2-(2-(N-phenyl-N-methylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.41(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.91(brs, 1H), 8.30(s, 1H), 7.93(d, J=8.4 Hz, 2H),7.76(d, J=8.4 Hz, 2H), 7.40(m, 5H), 7.16(t, J=8.4 Hz, 2H), 6.77(d, J=8.4Hz, 2H), 6.61(t, J=8.4 Hz, 1H), 4.50(t, J=6.0 Hz, 2H), 3.78(t, J=6.0 Hz,2H), 2.97(s, 3H), 2.34(s, 3H).

Example 5(17)6-phenyl-2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

NMR (CDCl₃): δ 8.21(s, 1H), 8.07(d, J=7.8 Hz, 2H), 7.75(d, J=7.8 Hz,2H), 7.48-7.29(m, 1H), 4.49(br, 2H), 4.00(br, 2H), 3.31(br, 3H), 2.41(s,3H).

REFERENCE EXAMPLE 32-bromo-6-methyl-3-(4-methylphenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using 2-bromo-3-amino-6-methylpyrazine in stead of2,6-dibromo-3-aminopyrazine, by the same procedure as a series ofreactions of Reference Example 1.

TLC: Rf 0.61(hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 10.82(br, 1H), 8.13(s, 1H), 7.85(d, J=8.1 Hz, 2H),7.37(d, J=8.1 Hz, 2H), 2.36(s, 3H), 2.35(s, 3H).

REFERENCE EXAMPLE 42-bromo-6-methyl-3-(N-(4-methylphenylsulfonyl)-N-(2-trimethylsilylethyl)amino)pyrazine

To a solution of the compound prepared in Reference Example 3 (1 g) and2-(trimethylsilyl)ethanol (0.628 mL) in methylene chloride (25 mL), 1.73mol/g polymer support triphenylphosphine (2.53 g, catalog number:800380, Argonaut Technologies) and diethyl azodicarboxylate (1.99 mL,40% toluene solution) were added at 0° C. The mixture was stirred for 2hours at 0° C. and overnight at room temperature. The reaction mixturewas filtered. The filtrate was concentrated. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=4:1→3:1) togive the title compound (320 mg) having the following physical data.

TLC: Rf 0.58(hexane:ethyl acetate=2:1);

NMR(CDCl₃): δ 7.92(d, J=8.4 Hz, 2H), 7.30(d, J=8.4 Hz, 2H), 7.15(s, 1H),3.69(m, 2H), 2.43(s, 3H), 2.34(s, 3H), 0.67(m, 2H), −0.07(s, 9H).

REFERENCE EXAMPLE 56-methyl-2-((3,4-dimethoxyphenyl)methyloxy)-3-(N-(4-methylphenylsulfonyl)-N-(2-trimethylsilylethyl)amino)pyrazine

The title compound having the following physical data was obtained,using the compound prepared in Reference Example 4, and3,4-dimethoxybenzyl alcohol in stead of benzyl alcohol, by the sameprocedure as a series of reactions of Example 1.

TLC: Rf 0.56(hexane:ethyl acetate=1:1).

EXAMPLE 66-methyl-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The compound prepared in Reference Example 5 was dissolved intoexcessive amounts of 1N tetrabutylammonium fluoride. The mixture wasstirred for 1 hour at room temperature and concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1→2:1) to give the title compound (88 mg) having the followingphysical data.

TLC: Rf 0.45(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.58(br, 1H), 7.82(d, J=8.1 Hz, 2H), 7.61(s, 1H),7.32(d, J=8.1 Hz, 2H), 7.13(d, J=1.5 Hz, 1H), 7.03(dd, J=8.1, 1.5 Hz,1H), 6.94(d, J=8.1 Hz, 1H), 5.27(s, 2H), 3.75(s, 3H), 3.74(s, 3H),2.34(s, 3H), 2.27(s, 3H).

Example 6(1)6-methyl-2-((3-(2-dimethylaminoethyloxy)-4-methoxyphenyl)methyloky)-3-(4-methylphenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using 3-(2-dimetylaminoethyl)oxy-4-methoxybenzyl alcohol in stead of3,4-dimethoxybenzyl alcohol, by the same procedure as a series ofreactions of Reference Example 5→Example 6.

TLC: Rf 0.36(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.78(d, J=8.1 Hz, 2H), 7.52(s, 1H), 7.28(d, J=8.1 Hz,2H), 7.15(d, J=1.8 Hz, 1H), 7.04(dd, J=8.1, 1.8 Hz, 1H), 6.95(d, J=8.1Hz, 1H), 5.23(s, 2H), 4.06(t, J=5.1 Hz, 2H), 3.75(s, 3H), 2.76(t, J=5.1Hz, 2H), 2.33(s, 3H), 2.32(s, 6H), 2.23(s, 3H).

REFERENCE EXAMPLE 66-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-aminopyrazine

The title compound having the following physical data was obtained,using 2,6-dibromo-3-aminopyrazine and 3,4-dimethoxybenzyl alcohol instead of benzyl alcohol, by the same procedure as a series of reactionsof Example 1.

TLC: Rf 0.35(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 7.60(s, 1H), 7.13(d, J=1.8 Hz, 1H), 7.02(dd, J=8.4, 1.8Hz, 1H), 6.93(d, J=8.4 Hz, 1H), 6.49(br, 2H), 3.76(s, 3H), 3.74(s, 3H).

EXAMPLE 76-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using the compound prepared in Reference Example 6 and4-chlorobenzenesulfonyl chloride in stead of 4-methylbenzenesulfonylchloride, by the same procedure as a series of reactions of ReferenceExample 1.

TLC: Rf 0.50(benzene:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.25(br, 1H), 7.92(m, 3H), 7.63(d, J=9.0 Hz, 2H),7.14(d, J=1.8 Hz, 1H), 7.04(dd, J=8.1, 1.8 Hz, 1H), 6.95(d, J=8.1 Hz,1H), 5.28(s, 2H), 3.75(s, 3H), 3.74(s, 3H).

Example 7(1)-7(4)

The following compounds were obtained, using the compound prepared inReference Example 6 and a corresponding sulfonyl chloride compound instead of 4-chlorobenzenesulfonyl chloride, by the same procedure as aseries of reactions of Example 7.

Example 7(1)6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(phenylsulfonylamino)pyrazine

TLC: Rf 0.52(benzene:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.15(br, 1H), 7.97-7.91(m, 3H), 7.64-7.53(m, 3H),7.15(d, J=2.1 Hz, 1H), 7.05(dd, J=8.4, 2.1 Hz, 1H), 6.95(d, J=8.4 Hz,1H), 5.28(s, 2H), 3.76(s, 3H), 3.75(s, 3H).

Example 7(2)6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

TLC: Rf 0.48(benzene:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.18(br, 1H), 8.01(m, 2H), 7.92(s, 1H), 7.40(t, J=8.7Hz, 2H), 7:14(d, J=2.4 Hz; 1H), 7.05(dd, J=8:1, 2.4 Hz, 1H), 6.96(d,J=8.4 Hz, 1H), 5.28(s, 2H), 3.76(s, 3H), 3.75(s, 3H).

Example 7(3)6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(2-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.60(benzene:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.10(br, 1H), 7.93(s, 1H), 7.75(m, 2H), 7.44(d, J=5.1Hz, 2H), 7.15(d, J=1.8 Hz, 1H), 7.05(dd, J=8.4, 1.8 Hz, 1H), 6.95(d,J=8.4 Hz, 1H), 5.28(s, 2H), 3.76(s, 3H), 3.75(s, 3H), 2.36(s, 3H).

Example 7(4)6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(3-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.60(benzene:ethyl acetate=3:1);

NMR(d₆-DMSO): δ 11.32(br, 1H), 7.92(m, 1H), 7.83(s, 1H), 7.50(dt, J=1.2,7.5 Hz, 1H), 7.35(m, 2H), 7.15(d, J=1.2 Hz, 1H), 7.03(dd, J=8.1, 1.8 Hz,1H), 6.95(d, J=8.1 Hz, 1H), 5.30(s, 2H), 3.76(s, 3H), 3.75(s, 3H),2.57(s, 3H).

EXAMPLE 86-(4-methylphenyl)-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of the compound prepared in Example 1(2) (70 mg),4-methylphenylboric acid (38 mg) and potassium carbonate (60 mg) in1,2-dimethoxyethane (1 mL) and water (0.5 mL),dichlorobis(triphenylphosphine)palladium (II) (4.9 mg, 5%N-methylpyrrolidone solution) was added. The mixture was stirred for 2hours at 80° C. 2N hydrochloric acid was added to the reaction mixture,and the mixture was extracted with chloroform. The extract was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=5:1→3:1) togive the title compound (48 mg) having the following physical data.

TLC: Rf 0.46(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.88(br, 1H), 8.31(s, 1H), 7.90(d, J=8.4 Hz, 2H),7.88(d, J=8.4 Hz, 2H), 7.36(d, J=8.1 Hz, 2H), 7.26(d, J=8.1 Hz, 2H),7.20(d, J=1.8 Hz, 1H), 7.08(dd, J=8.1, 1.8 Hz, 1H), 6.94(d, J=8.1 Hz,1H), 5.43(s, 2H), 3.73(s, 3H), 3.72(s, 3H), 2.35(s, 3H), 2.33(s, 3H).

Example 8(1)-8(3)

The following compounds were obtained, using a corresponding boric acidcompound in stead of 4-methylphenylboric acid, by the same procedure asa series of reactions of Example 8.

Example 8(1)6-(3-aminophenyl)-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.31(hexane:ethyl acetate=1:2);

NMR(d₆-DMSO): δ 8.17(s, 1H), 7.87(d, J=8.1 Hz, 2H), 7.35(d, J=7.8 Hz,2H), 7.23(d, J=9.3 Hz, 2H), 7.10(m, 3H), 6.94(d, J=8.1 Hz, 1H), 6.58(dt,J=7.5, 2.1 Hz, 1H), 5.42(s, 2H), 3.73(s, 6H), 2.35(s, 3H).

Example 8(2)6-(3-formylphenyl)-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.36(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 11.04(br, 1H), 10.07(s, 1H), 8.53(s, 1H), 8.44(s, 1H),8.33(d, J=7.8 Hz, 1H), 7.90(m, 3H), 7.68(t, J=7.8 Hz, 1H), 7.36(d, J=7.8Hz, 2H), 7.20(d, J=1.8 Hz, 1H), 7.12(dd, J=8.1, 1.8 Hz, 1H), 6.94(d,J=8.4 Hz, 1H), 5.46(s, 2H), 3.72(s, 6H), 2.35(s, 3H).

Example 8(3)6-(3-methoxyphenyl)-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

TLC: Rf 0.40(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.95(br, 1H), 8.35(s, 1H), 7.84(d, J=8.1 Hz, 2H),7.57(d, J=8.1 Hz, 1), 7.51(m, 1H), 7.35(m, 3H), 7.19(d, J=1.8 Hz, 1H),7.08(dd, J=7.8, 1.8 Hz, 1H), 6.94(m, 2H), 5.43(s, 2H), 3.79(s, 3H),3.72(s, 6H), 2.34(s, 3H).

EXAMPLE 92-((3-dimethylaminophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of the compound prepared in Example 3(5) (367 mg) inmethylene chloride (8 mL), 37% aqueous solution of formaldehyde (297 μL)was added at room temperature. Triacetoxy sodium borohydride (839 mg)was added to the mixture at 0° C. The mixture was stirred for 4 hours atroom temperature. Water was to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1) to give thetitle compound (328 mg) having the following physical data.

TLC: Rf 0.65(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 0.90(s, 1H), 7.88(d, J=8.1 Hz, 2H), 7.78-7.66(m, 2H),7.36(d, J=8.1 Hz, 2H), 7.17(t, J=8.4 Hz, 1H), 6.84(brs, 1H), 6.77(brd,J=7.8 Hz, 1H), 6.68(m, 1H), 5.33(s, 2H), 2.89(s, 6H), 2.36(s, 3H).

Example 9(1)6-(3-dimethylaminophenyl)-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The title compound having the following physical data was obtained,using the compound prepared in Example 8(1) in stead of the compoundprepared in Example 3(5) by the same procedure as a series of reactionsof Example 9.

TLC: Rf 0.47(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 10.90(br, 1H), 8.30(s, 1H), 7.88(d, J=8.4 Hz, 2H),7.36(d, J=8.4 Hz, 2H), 7.28-7.18(m, 4H), 7.07(dd, J=8.1, 1.2 Hz, 1H),6.92(d, J=8.1 Hz, 1H), 6.74(m, 1H), 5.44(s, 2H), 3.72(s, 6H), 2.93(s,6H), 2.35(s, 3H).

EXAMPLE 102-((3-acetylaminophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of the compound prepared in Example 3(5) (150 mg) inmethylene chloride (6 mL), pyridine (131 μL) and anhydrous acetic acid(76 μL) were added. The mixture was stirred for 2 hours at roomtemperature. Ethyl acetate was added to the reaction mixture. Themixture was washed with 2N hydrochloric acid, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:2) to give thetitle compound (153 mg) having the following physical data.

TLC: Rf 0.22(hexane:ethyl acetate=1:2);

NMR(d₆-DMSO): δ 10.92(s, 1H), 9.98(s, 1H), 7.88(d, J=8.4 Hz, 2H),7.80-7.68(m, 2H), 7.63(s, 1H), 7.56(d, J=7.5 Hz, 1H), 7.36(d, J=8.4 Hz,2H), 7.30(t, J=7.5 Hz, 1H), 7.17(d, J=7.5 Hz, 1H), 5.37(s, 2H), 2.36(s,3H), 2.04(s, 3H).

EXAMPLE 116-bromo-2-((3-(2-dimethylaminoethyloxy)-4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazinesodium salt

To a solution of the compound prepared in Example 1(3) (120 mg) inethanol (2 mL), 1N aqueous solution of sodium hydroxide (0.217 mL) wasadded. The mixture was stirred for 1 hour at 80° C. The reaction mixturewas concentrated to give the title compound (94 mg) having the followingphysical data.

TLC: Rf 0.32(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 7.62(d, J=8.4 Hz, 2H), 7.33(s, 1H), 7.10(m, 3H),7.00(dd, J=8.4, 18 Hz, 1H), 6.93(d, J=8.4 Hz, 1H), 5.08(s, 2H), 4.02(t,J=6.0 Hz, 2H), 3.74(s, 3H), 2.61(t, J=6.0 Hz, 2H), 2.27(s, 3H), 2.20(s,6H).

EXAMPLE 126-bromo-2-((pyridin-1-oxide-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of the compound prepared in Example 1(1) (500 mg) inchloroform (5 mL), 70% m-chloroperbenzoic acid (340 mg) was added. Themixture was stirred for 2 hours at room temperature. The reactionmixture was diluted with ethyl acetate. The diluted solution was washedwith a saturated solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:1→1:2→0:1→ethylacetate:methanol=5:1→3:1) to give the title compound (317 mg) having thefollowing physical data.

TLC: Rf 0.54(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.28(br, 1H), 8.58(s, 1H), 8.19(m, 1H), 7.89(s, 1H),7.83(d, J=8.1 Hz, 2H), 7.46(m, 2H), 7.34(d, J=8.1 Hz, 2H), 5.32(s, 2H),2.35(s, 3H).

EXAMPLE 136-bromo-2-((1-methylpyridinium-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazinechloride

To a solution of the compound prepared in Example 1(1) (300 mg) inacetone (5 mL), methyl iodide (64 μL) was added. The mixture was stirredovernight at room temperature. The reaction mixture was concentrated. Asolution of the residue in methanol was though chlorine ion-exchangeresin (preliminary washing: methanol×2, water×2, methanol×2) to give thetitle compound (288 mg) having the following physical data.

NMR(d₆-DMSO): δ 11.30(br, 1H), 9.38(s, 1H), 9.02(d, J=6.0 Hz, 1H),8.75(d, J=6.0 Hz, 1H), 8.20(dd, J=8.1, 6.0 Hz, 1H), 8.00(s, 1H), 7.89(d,J=8.1 Hz, 2H), 7.36(d, J=8.1 Hz, 2H), 5.58(s, 2H), 4.41(s, 3H), 2.35(s,3H).

REFERENCE EXAMPLE 7 2-chloro-3-(3-methylphenylsulfonylamino)quinoxaline

The title compound having the following physical data was obtained,using 2,3-dichloroquinoxaline in stead of 2,3-dichloropyrazine, and3-methylbenzenesulfonamide in stead of 4-methylbenzenesulfonamide, bythe same procedure as a series of reactions of Reference Example 2.

TLC: Rf 0.40(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 8.12 (m, 2H), 7.87 (m, 2H), 7.71 (t, J=7.8 Hz, 1H), 7.61(t, J=7.8 Hz, 1H), 7.42 (m, 2H), 2.45 (s, 3H).

REFERENCE EXAMPLE 8

wherein Pol is 1% divinylbenzene copolymer polystyrene resin.

Wang resin (Watanabe Chemical Co., Ltd., 1% divinylbenzene copolymerpolystyrene, 100-200 mesh, catalog number: A00110, 0.82 mmol/g, 4.0 g)was suspended in anhydrous tetrahydrofuran (40 mL). Under an atmosphereof argon, the compound prepared in Example 7 (1.82 g),triphenylphosphine (1.29 g) and 40% solution of diethyl azodicarboxylatein toluene (2.24 mL), successively, were added to the suspension at −78°C. The mixture was stirred for 16 hours at room temperature. Thereaction mixture was filtered. The obtained resin was washed withtetrahydrofuran (40 mL) for three times, methanol (40 mL) for two timesand methylene chloride (40 mL) for four times, successively, and driedto give the title compound (5.36 g).

REFERENCE EXAMPLE 9

Under an atmosphere of argon, to a suspension of the compound preparedin Reference Example 8 (750 mg) in anhydrous tetrahydrofuran (6 mL),2-phenoxyethanol (1.15 mL) and 1.0M tetrabutylammonium fluoride intetrahydrofuran solution (2.3 mL) were successively added at roomtemperature. The mixture was stirred for 24 hours at 60° C. The reactionmixture was cooled to room temperature, and filtered. The obtained resinwas washed with tetrahydrofuran (10 mL) for three times and methylenechloride (10 mL) for three times, successively, and dried to give thetitle compound (2) (834 mg).

EXAMPLE 142-(2-phenoxyethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

A suspension of the compound (2) prepared in Reference Example 9 (834mg) in 50% solution of trifluoroacetic acid in 1,2-dichloroethane (10mL) was stirred for 2 hours at room temperature. The reaction mixturewas filtered. The obtained resin was washed with 50% solution oftrifluoroacetic acid in 1,2-dichloroethane (10 mL) for three times. Thefiltrate and the washings were concentrated to give the title compound(168 mg) having the following physical data.

TLC: Rf 0.56(hexane:ethyl acetate=3:2);

NMR (d₆-DMSO): δ 11.34 (br, 1H), 8.10-7.85 (m, 2H), 7.84-7.62 (m, 2H),7.60-7.40 (m, 4H), 7.32 (t, J=8.1 Hz, 2H), 7.02 (d, J=8.1 Hz, 2H), 6.97(t, J=8.1 Hz, 1H), 4.77 (m, 2H), 4.45 (m, 2H), 2.41 (s, 3H);

HPLC maintenance time (minutes): 4.18;

Mass data: 893 (2M+Na)⁺, 436 (M+H)⁺.

Example 14(1)-14(210)

The following compounds were obtained, using 2,3-dichloroquinoxaline, acorresponding sulfonamide compound and a corresponding alcohol compound,by the same procedure as a series of reactions of Reference Example7→Reference Example 8→Reference Example 9→Example 14.

Example 14(1)2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.34;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(2)2-((pyridin-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.37;

Mass data: 835 (2M+Na)⁺, 407 (M+H)⁺.

Example 14(3)2-(2-(pyridin-2-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 863 (2M+Na)⁺, 421 (M+H)⁺.

Example 14(4)2-(3-(pyridin-3-yl)propyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass dada: 923-(2M+Na)⁺, 451 (M+H)⁺.

Example 14(5)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.50;

Mass data: 463 (M+H)⁺, 242.

Example 14(6)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.64;

Mass data: 449 (M+H)⁺.

Example 14(7)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.61;

Mass data: 438 (M+H)⁺.

Example 14(8)2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.15;

Mass data: 893 (2M+Na)⁺, 436 (M+H)⁺.

Example 14(9)2-(3-phenylpropyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.31;

Mass data: 889 (2M+Na)⁺, 434 (M+H)⁺.

Example 14(10)2-(4-phenylbutyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.40;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 14(11)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.17;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(12)2-(3-(pyridin-3-yl)propyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 435 (M+H)⁺.

Example 14(13)2-(3-benzyloxypropyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.23;

Mass data: 464 (M+H)⁺.

Example 14(14)2-(2-(pyridin-2-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.34;

Mass data: 421 (M+H)⁺.

Example 14(15)2-(3-(pyridin-2-yl)propyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 435 (M+H)⁺.

Example 14(16)2-(2-(pyridin-4-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 421 (M+H)⁺.

Example 14(17)2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.93;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 14(18)2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.47;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(19)2-(2-(piperidin-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.37;

Mass data: 427 (M+H)⁺.

Example 14(20)2-(2-cyclopentylethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.48;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(21)2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.30;

Mass data: 429 (M+H)⁺.

Example 14(22)2-(2-(pyrazol-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.75;

Mass data: 410 (M+H)⁺.

Example 14(23)2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.20;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 14(24)2-((pyridin-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 407 (M+H)⁺, 242.

Example 14(25)2-(2-cyclohexylethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.55;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(26)2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.42;

Mass data: 441 (M+H)⁺.

Example 14(27)2-(cyclopentylmethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.35;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 14(28)2-(2-phenylethyloxy)-3-(4-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.21;

Mass data: 420 (M+H)⁺.

Example 14(29)2-((pyridin-2-yl)methyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 393 (M+H)⁺, 302.

Example 14(30)2-((pyridin-2-yl)methyloxy)-3-(2-methylphenylsulfonylammo)quinoxaline

HPLC maintenance time (minutes): 3.38;

Mass data: 407 (M+H)⁺, 316.

Example 14(31)2-((pyridin-2-yl)methyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.42;

Mass data: 407 (M+H)⁺.

Example 14(32)2-((pyridin-2-yl)methyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 423 (M+H)⁺.

Example 14(33)2-(2-cyclohexylethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.48;

Mass data: 412 (M+H)⁺.

Example 14(34)2-(2-cyclohexylethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.57;

Mass data: 426 (M+H)⁺.

Example 14(35)2-(2-cyclohexylethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.59;

Mass data: 426 (M+H)⁺.

Example 14(36)2-(2-cyclohexylethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.50;

Mass data: 442 (M+H)⁺.

Example 14(37)2-(3-(piperidin-1-yl)propyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 427 (M+H)⁺.

Example 14(38)2-(3-(piperidin-1-yl)propyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 441 (M+H)⁺.

Example 14(39)2-(3-(piperidin-1-yl)propyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.42;

Mass data: 441 (M+H)⁺.

Example 14(40)2-(3-(piperidin-1-yl)propyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 457 (M+H)⁺.

Example 14(41)2-(cyclopentylmethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.26;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 14(42)2-(cyclopentylmethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.35;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 14(43)2-(cyclopentylmethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.35;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 14(44)2-(cyclopentylmethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.28;

Mass data: 849 (2M+Na)⁺, 414 (M+H)⁺.

Example 14(45) 2-(2-pneylethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.13;

Mass data: 833 (2M+Na)⁺, 406 (M+H)⁺.

Example 14(46)2-(2-phenylethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.22;

Mass data: 861 (2M+Na)⁺, 420 (M+H)⁺.

Example 14(47)2-(2-phenylethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.23;

Mass data: 861 (2M+Na)⁺, 420 (M+H)⁺.

Example 14(48)2-(2-phenylethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.15;

Mass data: 893 (2M+Na)⁺, 436 (M+H)⁺.

Example 14(49)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.49;

Mass data: 463 (M+H)⁺.

Example 14(50)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.49;

Mass data: 463 (M+H)⁺.

Example 14(51)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 449 (M+H)⁺.

Example 14(52)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.42;

Mass data: 479 (M+H)⁺.

Example 14(53)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.67;

Mass data: 449 (M+H)⁺.

Example 14(54)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.67;

Mass data: 449 (M+H)⁺.

Example 14(55)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.58;

Mass data: 435 (M+H)⁺.

Example 14(56)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.62;

Mass data: 465 (M+H)⁺.

Example 14(57)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.60;

Mass data: 897 (2M+Na)⁺, 438 (M+H)⁺.

Example 14(58)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.64;

Mass data: 897 (2M+Na)⁺, 438 (M+H)⁺.

Example 14(59)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.51;

Mass data: 869 (2M+Na)⁺, 424 (M+H)⁺.

Example 14(60)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.55;

Mass data: 929 (2M+Na)⁺, 454 (M+H)⁺.

Example 14(61)2-(2-phenoxyethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.15;

Mass data: 893 (2M+Na)⁺, 436 (M+H)⁺.

Example 14(62)2-(3-benzyloxypropyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.22;

Mass data: 949 (2M+Na)⁺, 464 (M+H)⁺.

Example 14(63) 2-(2-phenoxyethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.06;

Mass data: 865 (2M+Na)⁺, 422 (M+H)⁺.

Example 14(64)2-(2-phenoxyethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.08;

Mass data: 925 (2M+Na)⁺, 452 (M+H)⁺.

Example 14(65)2-(3-phenylpropyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.32;

Mass data: 889 (2M+Na)⁺, 434 (M+H)⁺, 120.

Example 14(66)2-(3-phenylpropyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.32;

Mass data: 889 (2M+Na)⁺, 434 (M+H)⁺, 120.

Example 14(67) 2-(3-phenylpropyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.22;

Mass data: 861 (2M+Na)⁺, 420 (M+H)⁺, 120.

Example 14(68)2-(3-phenylpropyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.24;

Mass data: 921 (2M+Na)⁺, 450 (M+H)⁺, 120.

Example 14(69)2-(4-phenylbutyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.39;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 14(70)2-(4-phenylbutyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.41;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 14(71) 2-(4-phenylbutyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.32;

Mass data: 889 (2M+Na)⁺, 434 (M+H)⁺.

Example 14(72)2-(4-phenylbutyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.32;

Mass data: 949 (2M+Na)⁺, 464 (M+H)⁺.

Example 14(73)2-(2-(thiophen-2-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.17;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(74)2-(2-(thiophen-2-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.17;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(75)2-(2-(thiophen-2-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.09;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(76)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.10;

Mass data: 905 (2M+Na)⁺, 442 (M+H)⁺.

Example 14(77)2-(3-(pyridin-3-yl)propyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.38;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(78)2-(3-(pyridin-3-yl)propyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(79)2-(3-(pyridin-3-yl)propyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 863 (2M+Na)⁺, 421 (M+H)⁺.

Example 14(80)2-(3-benzyloxypropyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.22;

Mass data: 949 (2M+Na)⁺, 464 (M+H)⁺.

Example 14(81)2-(3-benzyloxypropyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.13;

Mass data: 921 (2M+Na)⁺, 450 (M+H)⁺.

Example 14(82)2-(3-(benzyloxy)propyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.13;

Mass data: 981 (2M+Na)⁺, 480 (M+H)⁺.

Example 14(83)2-(2-(pyridin-2-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.34;

Mass data: 863 (2M+Na)⁺, 421 (M+H)⁺.

Example 14(84)2-(2-(pyridin-2-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 835 (2M+Na)⁺, 407 (M+H)⁺.

Example 14(85)2-(2-(pyridin-2-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.31;

Mass data: 895 (2M+Na)⁺, 437 (M+H)⁺.

Example 14(86)2-(3-(pyridin-2-yl)propyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(87)2-(3-(pyridin-2-yl)propyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.38;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(88)2-(3-(pyridin-2-yl)propyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.31;

Mass data: 863 (2M+Na)⁺, 421 (M+H)⁺.

Example 14(89)2-(3-(pyridin-2-yl)propyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 923 (2M+Na)⁺, 451 (M+H)⁺, 332.

Example 14(90)2-(2-(pyridin-4-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 841 (2M+H)⁺, 421 (M+H)⁺.

Example 14(91)2-(2-(pyridin-4-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.34;

Mass data: 841 (2M+H)⁺, 421 (M+H)⁺.

Example 14(92)2-(2-(pyridin-4-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(93)2-(2-(pyridin-4-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 873 (2M+H)⁺, 437 (M+H)⁺.

Example 14(94)2-((tetrahydrofuran-2-yl)methyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.93;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 14(95)2-((tetrahydrofuran-2-yl)methyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.93;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 14(96)2-((tetrahydrofuran-2-yl)methyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.82;

Mass data: 793 (2M+Na)⁺, 386 (M+H)⁺.

Example 14(97)2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.84;

Mass data: 853 (2M+Na)⁺, 416 (M+H)⁺.

Example 14(98)2-(cyclohexylmethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.50;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(99)2-((cyclohexyl)methyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.48;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(100)2-(cyclohexylmethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.37;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 14(101)2-(cyclohexylmethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.39;

Mass data: 877 (2M+Na)⁺, 428 (M+H)⁺.

Example 14(102)2-(2-(piperidin-1-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.35;

Mass data: 427 (M+H)⁺.

Example 14(103)2-(2-(piperidin-1-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 427 (M+H)⁺.

Example 14(104)2-(2-(piperidin-1-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 413 (M+H)⁺.

Example 14(105)2-(2-(piperidin-1-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 443 (M+H)⁺.

Example 14(106)2-(2-cyclopentylethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.46;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(107)2-(2-cyclopentylethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.46;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(108)2-(2-cyclopentylethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.37;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 14(109)2-(2-cyclopentylethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.39;

Mass data: 877 (2M+Na)⁺, 428 (M+H)⁺.

Example 14(110)2-(2-(morpholin-4-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 879 (2M+Na)⁺, 429 (M+H)⁺.

Example 14(111)2-(2-(morpholin-4-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 879 (2M+Na)⁺, 429 (M+H)⁺.

Example 14(112)2-(2-(morpholin-4-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.22;

Mass data: 415 (M+H)⁺.

Example 14(113)2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.25;

Mass data: 911 (2M+Na)⁺, 445 (M+H)⁺.

Example 14(114)2-(2-(pyrazol-1-yl)ethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.77;

Mass data: 841 (2M+Na)⁺, 410 (M+H)⁺.

Example 14(115)2-(2-(pyrazol-1-yl)ethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.77;

Mass data: 841 (2M+Na)⁺, 410 (M+H)⁺.

Example 14(116)2-(2-(pyrazol-1-yl)ethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.67;

Mass data: 813 (2M+Na)⁺, 396 (M+H)⁺.

Example 14(117)2-(2-(pyrazol-1-yl)ethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.71;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(118)2-(2-cyclopropylethyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.21;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 14(1-19)2-(2-cyclopropylethyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.21;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 14(120)2-(2-cyclopropylethyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.10;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺.

Example 14(121)2-(2-cyclopropylethyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.11;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 14(122)2-((pyridin-3-yl)methyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(123)2-((pyridin-3-yl)methyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(124)2-((pyridin-3-yl)methyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 785 (2M+H)⁺, 393 (M+H)⁺.

Example 14(125)2-((pyridin-3-yl)methyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 845 (2M+H)⁺, 423 (M+H)⁺.

Example 14(126)2-((pyridin-4-yl)methyloxy)-3-(2-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.31;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(127)2-((pyridin-4-yl)methyloxy)-3-(3-methylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 813 (2M+H)⁺, 407 (M+H)⁺.

Example 14(128)2-((pyridin-4-yl)methyloxy)-3-(phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.25;

Mass data: 785 (2M+H)⁺, 393 (M+H)⁺.

Example 14(129)2-((pyridin-4-yl)methyloxy)-3-(4-methoxyphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 845 (2M+H)⁺, 423 (M+H)⁺.

Example 14(130)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 474 (M+H)⁺.

Example 14(131)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.55;

Mass data: 529 (M+H)⁺.

Example 14(132)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-cyanophenylsulfonylaminoquinoxaline

HPLC maintenance time (minutes): 3.62;

Mass data: 460 (M+H)⁺.

Example 14(133)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.78;

Mass data: 513 (M+H)⁺.

Example 14(134)2-(2-phenoxyethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.04;

Mass data: 469 (M+Na)⁺, 447 (M+H)⁺.

Example 14(135)2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.26;

Mass data: 522 (M+Na)⁺, 500 (M+H)⁺.

Example 14(136)2-(3-phenylpropyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.21;

Mass data: 467 (M+Na)⁺, 445 (M+H)⁺.

Example 14(137)2-(3-phenylpropyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.43;

Mass data: 520 (M+Na)⁺, 498 (M+H)⁺.

Example 14(138)2-(4-phenylbutyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.28;

Mass data: 481 (M+Na)⁺, 459 (M+H)⁺.

Example 14(139)2-(4-phenylbutyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.52;

Mass data: 534 (M+Na)⁺, 512 (M+H)⁺.

Example 14(140)2-(3-(pyridin-3-yl)propyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 446 (M+H)⁺.

Example 14(141)2-(3-(pyridin-3-yl)propyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.47;

Mass data: 499 (M+H)⁺.

Example 14(142)2-(3-benzyloxypropyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.11;

Mass data: 497 (M+Na)⁺, 475 (M+H)⁺.

Example 14(143)2-(3-benzyloxypropyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.34;

Mass data: 550 (M+Na)⁺, 528 (M+H)⁺.

Example 14(144)2-(2-(pyridin-2-yl)ethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 432 (M+H)⁺.

Example 14(145)2-(2-(pyridin-2)ethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.42;

Mass data: 485 (M+H)⁺.

Example 14(146)2-(3-(pyridin-2-yl)propyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.31;

Mass data: 446 (M+H)⁺.

Example 14(147)2-(3-(pyridin-2-yl)propyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.47;

Mass data: 499 (M+H)⁺.

Example 14(148)2-(2-(pyridin-4-yl)ethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.27;

Mass data: 432 (M+H)⁺.

Example 14(149)2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.82;

Mass data: 433 (M+Na)⁺, 411 (M+H)⁺.

Example 14(150)2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.06;

Mass data: 486 (M+Na)⁺, 464 (M+H)⁺.

Example 14(151)2-(cyclohexylmethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.35;

Mass data: 423 (M+H)⁺.

Example 14(152)2-(cyclohexylmethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.59;

Mass data: 476 (M+H)⁺.

Example 14(153)2-(2-(piperidin-1-yl)ethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.29;

Mass data: 438 (M+H)⁺.

Example 14(154)2-(2-(piperidin-1-yl)ethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.44;

Mass data: 491 (M+H)⁺.

Example 14(155)2-(2-cyclopentylethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.33;

Mass data: 423 (M+H)⁺.

Example 14(156)2-(2-cyclopentylethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.59;

Mass data: 476 (M+H)⁺.

Example 14(157)2-(2-(morpholin-4-yl)ethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.22;

Mass data: 440 (M+H)⁺.

Example 14(158)2-(2-(morpholin-4-yl)ethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.36;

Mass data: 493 (M+H)⁺.

Example 14(159)2-(2-cyclopropylethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.08;

Mass data: 395 (M+H)⁺.

Example 14(160)2-(2-cyclopropylethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.33;

Mass data: 448 (M+H)⁺.

Example 14(161)2-((pyridin-2-yl)methyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.34;

Mass data: 418 (M+H)⁺.

Example 14(162)2-((pyridin-2-yl)methyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.53;

Mass data: 471 (M+H)⁺.

Example 14(163)2-(2-cyclohexylethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.45;

Mass data: 437 (M+H)⁺.

Example 14(164)2-(2-cyclohexylethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.72;

Mass data: 490 (M+H)⁺.

Example 14(165)2-(3-(piperidin-1-yl)propyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.33;

Mass data: 452 (M+H)⁺.

Example 14(166)2-(3-(piperidin-1-yl)propyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.49;

Mass data: 505 (M+H)⁺.

Example 14(167)2-(2-phenylethyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.10;

Mass data: 453 (M+Na)⁺, 431 (M+H)⁺.

Example 14(168)2-(2-phenylethyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.34;

Mass data: 506 (M+Na)⁺, 484 (M+H)⁺.

Example 14(169)2-((pyridin-3-yl)methyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.25;

Mass data: 418 (M+H)⁺.

Example 14(170)2-((pyridin-3-yl)methyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 471 (M+H)⁺.

Example 14(171)2-((pyridin-4-yl)methyloxy)-3-(4-cyanophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.25;

Mass data: 418 (M+H)⁺.

Example 14(172)2-((pyridin-4-yl)methyloxy)-3-(4-bromophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.40;

Mass data: 471 (M+H)⁺.

Example 14(173)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.80;

Mass data: 453 (M+H)⁺.

Example 14(174)2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.28;

Mass data: 901 (2M+Na)⁺, 440 (M+H)⁺.

Example 14(175)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 881 (2M+Na)⁺, 430 (M+H)⁺.

Example 14(176)2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.50;

Mass data: 825 (2M+Na)⁺, 402 (M+H)⁺.

Example 14(177)2-(2-phenylethyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.35;

Mass data: 869 (2M+Na)⁺, 424 (M+H)⁺.

Example 14(178)2-((pyridin-3-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.44;

Mass data: 821 (2M+H)⁺, 411 (M+H)⁺.

Example 14(179)2-((pyridin-4-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.44;

Mass data: 411 (M+H)⁺.

Example 14(180)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.91;

Mass data: 469 (M+H)⁺.

Example 14(181)2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.41;

Mass data: 933 (2M+Na)⁺, 456 (M+H)⁺.

Example 14(182)2-((pyridin-2-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.64;

Mass data: 875 (2M+Na)⁺, 427 (M+H)⁺.

Example 14(183)2-(cyclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.63;

Mass data: 857 (2M+Na)⁺, 418 (M+H)⁺.

Example 14(184)2-(2-phenylethyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.48;

Mass data: 901 (2M+Na)⁺, 440 (M+H)⁺.

Example 14(185)2-((pyridin-3-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.55;

Mass data: 427 (M+H)⁺.

Example 14(186)2-((pyridin-4-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.55;

Mass data: 427 (M+H)⁺.

Example 14(187)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.93;

Mass data: 463 (M+H)⁺.

Example 14(188)2-(2-phenoxyethyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.43;

Mass data: 921 (2M+Na)⁺, 450 (M+H)⁺.

Example 14(189)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.46;

Mass data: 901 (2M+Na)⁺, 440 (M+H)⁺.

Example 14(190)2-((pyridin-2-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.66;

Mass data: 863 (2M+Na)⁺, 421 (M+H)⁺.

Example 14(191)2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.65;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 14(192)2-(2-phenylethyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.50;

Mass data: 889 (2M+Na)⁺, 434 (M+H)⁺.

Example 14(193)2-((pyridin-3-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.58;

Mass data: 841 (2M+H)⁺, 421 (M+H)⁺.

Example 14(194)2-((pyridin-4-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.56;

Mass data: 841 (2M+H)⁺, 421 (M+H)⁺.

Example 14(195)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.04;

Mass data: 477 (M+H)⁺.

Example 14(196)2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.52;

Mass data: 949 (2M+Na)⁺, 464 (M+H)⁺.

Example 14(197)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.55;

Mass data: 929 (2M+Na)⁺, 454 (M+H)⁺.

Example 14(198)2-((pyridin-2-yl)methyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.77;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(199)2-(cyclopentylmethyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.76;

Mass data: 873 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(200)2-(2-phenylethyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.61;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 14(201)2-((pyridin-3-yl)methyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.66;

Mass data: 869 (2M+H)⁺, 435 (M+H)⁺.

Example 14(202)2-((pyridin-4-yl)methyloxy)-3-(4-propylphenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.67;

Mass data: 869 (2M+H)⁺, 435 (M+H)⁺.

Example 14(203)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.04;

Mass data: 975 (M+Na)⁺, 477 (M+H)⁺.

Example 14(204)2-(2-phenoxyethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.48;

Mass data: 949 (2M+H)⁺, 464 (M+H)⁺.

Example 14(205)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.54;

Mass data: 929 (2M+Na)⁺, 454 (M+H)⁺.

Example 14(206)2-((pyridin-2-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.75;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

Example 14(207)2-(cyclopentylmethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.74;

Mass data: 874 (2M+Na)⁺, 426 (M+H)⁺.

Example 14(208)2-(2-phenylethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 4.59;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 14(209)2-((pyridin-3-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.66;

Mass data: 869 (2M+H)⁺, 435 (M+H)⁺.

Example 14(210)2-((pyridin-4-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)quinoxaline

HPLC maintenance time (minutes): 3.66;

Mass data: 891 (2M+Na)⁺, 435 (M+H)⁺.

REFERENCE EXAMPLE 10

The compound (3) was obtained, using a compound prepared in ReferenceExample 2 in stead of a compound prepared in Reference Example 7 by thesame procedure as a series of reactions of Reference Example 8.

EXAMPLE 15 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

Under an atmosphere of argon, to a suspension of the compound (3)prepared in Reference Example 10 (100 mg) in anhydrous 1,4-dioxane (2mL), 2-phenoxyethanol (0.214 mL) and 16M n-butyl lithium-hexane solution(0.267 mL) were successively added at room temperature. The mixture wasstirred foe 16 hours at 100° C. The reaction mixture was cooled to roomtemperature and filtered. The obtained resin was washed withtetrahydrofuran (2 mL) for two times, methanol (2 mL) for four times andmethylene chloride (2 mL) for five times. The title compound (26 mg)having the following physical data was obtained by the same procedure asa series of reactions of Example 14.

TLC: Rf 0.89(chloroform:methanol=10:1); —NMR(d₆-DMSO): δ 10.88 (s, 1H),7.86 (d, J=8.4 Hz, 2H), 7.71—(m, 2H), 7.34 (d, J=8.4 Hz; 2H), 7.29 (dd,J=7.8, 7.2 Hz, 2H), 6.97 (d, J=7.8 Hz, 2H), 6.94 (t, J=7.2 Hz, 1H), 4.60(m, 2H), 4.34 (m, 2H), 2.34 (s, 3H);

HPLC maintenance time (minutes): 3.89;

Mass data: 771 (2M+H)⁺, 386 (M+H)⁺.

Example 15(1)-15(63)

The following compounds were obtained, using 2,3-dichloropyrazine, acorresponding sulfonamide compound and a corresponding alcohol compound,by the same procedure as a series of reactions of Reference Example2→Reference Example 10→Example 15.

Example 15(1)2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 413 (M+H)⁺.

Example 15(2)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 819 (2M+Na)⁺, 399 (M+H)⁺.

Example 15(3)2-(2-(3,5-dimethylpyrazol-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.29;

Mass data: 797 (2M+Na)⁺, 388 (M+H)⁺.

Example 15(4)2-(3-benzyloxypropyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.98;

Mass data: 414 (M+H)⁺.

Example 15(5)2-(3-phenylpropyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.08;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 15(6)2-(4-phenylbutyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.16;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 15(7)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.92;

Mass data: 773 (2M+Na)⁺, 376 (M+H)⁺.

Example 15(8)2-(3-(pyridin-3-yl)propyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.21;

Mass data: 769 (2M+H)⁺, 385 (M+H)⁺.

Example 15(9)2-(3-(pyridin-2-yl)propyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.20;

Mass data: 385 (M+H)⁺.

Example 15(10)2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.60;

Mass data: 721 (2M+Na)⁺, 350 (M+H)⁺.

Example 15(11)2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 745 (2M+Na)⁺, 362 (M+H)⁺.

Example 15(12)2-(2-(piperidin-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.19;

Mass data: 377 (M+H)⁺.

Example 15(13)2-(2-cyclopentylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.20;

Mass data: 745 (2M+Na)⁺, 362 (M+H)⁺.

Example 15(14)2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 379 (M+H)⁺.

Example 15(15)2-(2-(pyrazol-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.46;

Mass data: 741 (2M+Na)⁺, 360 (M+H)⁺.

Example 15(16)2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.91;

Mass data: 689 (2M+Na)⁺, 334 (M+H)⁺.

Example 15(17)2-((pyridin-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 735 (2M+Na)⁺, 357 (M+H)⁺.

Example 15(18)2-(2-cyclohexylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 773 (2M+Na)⁺, 376 (M+H)⁺.

Example 15(19)2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.22;

Mass data: 391 (M+H)⁺.

Example 15(20)2-(cyclopentylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.07;

Mass data: 717 (2M+Na)⁺, 348 (M+H)⁺.

Example 15(21)2-(2-phenylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.96;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺.

Example 15(22)2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.15;

Mass data: 713 (2M+H)⁺, 357 (M+H)⁺.

Example 15(23)2-((pyridin-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.14;

Mass data: 713 (2M+H)⁺, 357 (M+H)⁺.

Example 15(24)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 403 (M+H)⁺.

Example 15(25)2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.99;

Mass data: 801 (2M+Na)⁺, 390 (M+H)⁺.

Example 15(26)2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.17;

Mass data: 725 (2M+Na)⁺, 352 (M+H)⁺, 270.

Example 15(27)2-(2-phenylethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.06;

Mass data: 769 (2M+Na)⁺, 374 (M+H)⁺.

Example 15(28)2-((pyridin-3-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.19;

Mass data: 361 (M+H)⁺.

Example 15(29)2-((pyridin-4-yl)methyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.19;

Mass data: 361 (M+H)⁺.

Example 15(30)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 419 (M+H)⁺.

Example 15(31)2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.12;

Mass data: 406 (M+H)⁺.

Example 15(32)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.13;

Mass data: 396 (M+H)⁺.

Example 15(33)2-(cyclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.30;

Mass data: 757 (2M+Na)⁺, 368 (M+H)⁺.

Example 15(34)2-(2-phenylethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.19;

Mass data: 801 (2M+Na)⁺, 390 (M+H)⁺.

Example 15(35)2-((pyridin-3-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.30;

Mass data: 753 (2M+H)⁺, 377 (M+H)⁺.

Example 15(36)2-((pyridin-4-yl)methyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.30;

Mass data: 377 (M+H)⁺.

Example 15(37)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.64;

Mass data: 463 (M+H)⁺.

Example 15(38)2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.16;

Mass data: 450 (M+H)⁺.

Example 15(39)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.17;

Mass data: 440 (M+H)⁺.

Example 15(40)2-((pyridin-2-yl)methyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.37;

Mass data: 421 (M+H)⁺.

Example 15(41)2-(cyclopentylmethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.33;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 15(42)2-(2-phenylethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 434 (M+H)⁺.

Example 15(43)2-((pyridin-3-yl)methyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 421 (M+H)⁺.

Example 15(44)2-((pyridin-4-yl)methyloxy)-3-(4-bromophenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 421 (M+H)⁺.

Example 15(45)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.62;

Mass data: 413 (M+H)⁺.

Example 15(46)2-(2-phenoxyethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.15;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 15(47)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.15;

Mass data: 801 (2M+Na)⁺, 390 (M+H)⁺.

Example 15(48)2-((pyridin-2-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 763 (2M+Na)⁺, 371 (M+H)⁺.

Example 15(49)2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.33;

Mass data: 745 (2M+Na)⁺, 362 (M+H)⁺, 280.

Example 15(50)2-(2-phenylethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 15(51)2-((pyridin-3-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.34;

Mass data: 741 (2M+H)⁺, 371 (M+H)⁺.

Example 15(52)2-((pyridin-4-yl)methyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 763 (2M+Na)⁺, 371 (M+H)⁺.

Example 15(53)2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.77;

Mass data: 875 (2M+Na)⁺, 427 (M+H)⁺.

Example 15(54)2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.25;

Mass data: 849 (2M+Na)⁺, 414 (M+H)⁺.

Example 15(55)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.28;

Mass data: 829 (2M+Na)⁺, 404 (M+H)⁺.

Example 15(56)2-((pyridin-2-yl)methyloxy)-3-(4-propylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 791 (2M+Na)⁺, 385 (M+H)⁺.

Example 15(57)2-(2-phenoxyethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 849 (2M+Na)⁺, 414 (M+H)⁺.

Example 15(58)2-(2-(thiophen-2-yl)ethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.26;

Mass data: 829 (2M+Na)⁺, 404 (M+H)⁺.

Example 15(59)2-((pyridin-2-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 791 (2M+Na)⁺, 385 (M+H)⁺.

Example 15(60)2-(cyclopentylmethyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.41;

Mass data: 773 (2M+Na)⁺, 376 (M+H)⁺.

Example 15(61)2-(2-phenylethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.30;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 15(62)2-((pyridin-3-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.44;

Mass data: 769 (2M+H)⁺, 385 (M+H)⁺.

Example 15(63)2-((pyridin-4-yl)methyloxy)-3-(4-(1-methylethyl)phenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 791 (2M+Na)⁺, 385 (M+H)⁺.

REFERENCE EXAMPLE 11

The compound (4) was obtained, using the compound prepared in Example1(1) in stead of the compound prepared in Reference Example 7, by thesame procedure as a series of reactions of Reference Example 8.

EXAMPLE 166-phenyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

Under an atmosphere of argon, to a suspension of the compound (4)prepared in Reference Example 11 (50 mg) in 1,2-dimethoxyethane (1 mL),phenylboric acid (28 mg), 2N aqueous solution of sodium carbonate (0.30mL) and dichlorobis(triphenylphosphine)palladium (II) (4.3 mg),successively, were added at room temperature. The mixture was stirredfor 6 hours at 90° C. The reaction mixture was cooled to roomtemperature, and filtered. The obtained resin was washed with a mixtureof 1,2-dimethoxyethane and water (2 mL) for two times, water (2 mL) fortwo times, a mixture of 1,2-dimethoxyethane and water (2 mL) for threetimes, a mixture of 0.2N hydrochloric acid and tetrahydrofuran (1:2)(2mL) for three times, a mixture of water and tetrahydrofuran (12) (2 mL)for three times, tetrahydrofuran (2 mL) for three times, and1,2-dichloroethane (2 mL) for three times. The title compound (11 mg)having the following physical data was obtained by the same procedure asa series of reactions of Example 14.

TLC: Rf 0.70(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 11.05 (brs, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.54 (dd,J=3.9, 2.1 Hz, 1H), 8.37 (s, 1H), 7.99 (dd, J=3.9, 1.8 Hz, 3H), 7.89 (d,J=8.1 Hz, 2H), 7.45-7.36 (m, 6H), 5.56 (s, 2H), 2.35 (s, 3H);

HPLC maintenance time (minutes): 3.49;

Mass condition: ESI (Pos., 40 V);

Mass data: 433 (M+H)⁺.

Example 16(1)-16(60)

The following compounds were obtained, using a corresponding boric acidcompound in stead of phenylboric acid, by the same procedure as a seriesof reactions of Example 16.

Example 16(1)6-(3-nitrophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 955 (2M+H)⁺, 478 (M+H)⁺.

Example 16(2)6-(2,4-dichlorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.71;

Mass data: 501 (M+H)⁺.

Example 16(3)6-(naphthalen-1-yl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.62;

Mass data: 965 (2M+H)⁺, 483 (M+H)⁺.

Example 16(4)6-(4-fluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.53;

Mass data: 901 (2M+H)⁺, 451 (M+H)⁺.

Example 16(5)6-(4-chlorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.62;

Mass data: 933 (2M+H)⁺, 467 (M+H)⁺.

Example 16(6)6-(4-methylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 893 (2M+H)⁺, 447 (M+H)⁺.

Example 16(7)6-(4-methoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 925 (2M+H)⁺, 463 (M+H)⁺.

Example 16(8)6-(3-methylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 893 (2M+H)⁺, 447 (M+H)⁺.

Example 16(9)6-(3-chloro-4-fluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.64;

Mass data: 969 (2M+H)⁺, 485 (M+H)⁺.

Example 16(10)6-(3,5-bis(trifluoromethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.80;

Mass data: 569 (M+H)⁺.

Example 16(11)6-(3,5-dichloromethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.75;

Mass data: 501 (M+H)⁺.

Example 16(12)6-(4-phenylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.77;

Mass data: 509 (M+H)⁺.

Example 16(13)6-(4-methylthiophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.60;

Mass data: 957 (2M+H)⁺, 479 (M+H)⁺.

Example 16(14)6-(2-methylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 893 (2M+H)⁺, 447 (M+H)⁺.

Example 16(15)6-(phenanthren-9-yl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.80;

Mass data: 533 (M+H)⁺.

Example 16(16)6-(3-aminophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.09;

Mass data: 895 (2M+H)⁺, 448 (M+H)⁺.

Example 16(17)6-(4-carboxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 953 (2M+H)⁺, 477 (M+H)⁺.

Example 16(18)6-(2-formylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 921 (2M+H)⁺, 461 (M+H)⁺.

Example 16(19)6-(3-trifluoromethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.66;

Mass data: 501 (M+H)⁺.

Example 16(20)6-(4-trifluoromethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.67;

Mass data: 501 (M+H)⁺.

Example 16(21)6-(3-formylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 921 (2M+H)⁺, 461 (M+H)⁺.

Example 16(22)6-(3-methoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 925 (2M+H)⁺, 463 (M+H)⁺.

Example 16(23)6-(3-nitro-4-methylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance-time (minutes): 3.56;

Mass data: 983 (2M+H)⁺, 492 (M+H)⁺.

Example 16(24)6-(3-acetylaminophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.31;

Mass data: 979 (2M+H)⁺, 490 (M+H)⁺.

Example 16(25)6-(3-fluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.53;

Mass data: 901 (2M+H)⁺, 451 (M+H)⁺.

Example 16(26)6-(2-methoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.51;

Mass data: 925 (2M+H)⁺, 463 (M+H)⁺.

Example 16(27)6-(naphthalen-2-yl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.66;

Mass data: 965 (2M+H)⁺, 483 (M+H)⁺.

Example 16(28)6-(2-trifluoromethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 501 (M+H)⁺.

Example 16(29)6-(3-ethoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.60;

Mass data: 953 (2M+H)⁺, 477 (M+H)⁺.

Example 16(30)6-(2-chlorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.56;

Mass data: 933 (2M+H)⁺, 467 (M+H)⁺.

Example 16(31)6-(2-fluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.51;

Mass data: 901 (2M+H)⁺, 451 (M+H)⁺.

Example 16(32)6-(4-ethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.67;

Mass data: 921 (2M+H)⁺, 461 (M+H)⁺.

Example 16(33)6-(3,4-dimethylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.66;

Mass data: 921 (2M+H)⁺, 461 (M+H)⁺.

Example 16(34)6-(1,3-dioxaindan-5-yl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.49;

Mass data: 953 (2M+H)⁺, 477 (M+H)⁺.

Example 16(35)6-(4-(1,1-dimethylethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.82;

Mass data: 977 (2M+H)⁺, 489 (M+H)⁺.

Example 16(36)6-(3,4-dimethoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 985 (2M+H)⁺, 493 (M+H)⁺.

Example 16(37)6-(2,4-dimethoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.53;

Mass data: 985 (2M+H)⁺, 493 (M+H)⁺.

Example 16(38)6-(4-(1-methylethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.75;

Mass data: 949 (2M+H)⁺, 475 (M+H)⁺.

Example 16(39)6-(4-hydroxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.31;

Mass data: 897 (2M+H)⁺, 449 (M+H)⁺.

Example 16(40)6-(3-(1-methylethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.73;

Mass data: 949 (2M+H)⁺, 475 (M+H)⁺.

Example 16(41)6-(4-methylcarbonylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 949 (2M+H)⁺, 475 (M+H)⁺.

Example 16(42)6-(3-methylcarbonylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.44;

Mass data: 949 (2M+H)⁺, 475 (M+H)⁺.

Example 16(43)6-(3,4,5-trimethoxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.45;

Mass data: 523 (M+H)⁺.

Example 16(44)6-(2,3-dichlorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.66;

Mass data: 501 (M+H)⁺.

Example 16(45)6-(4-(2-carboxyethenyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 503 (M+H)⁺.

Example 16(46)6-(4-benzyloxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.78;

Mass data: 539 (M+H)⁺.

Example 16(47)6-(4-phenyl-3-fluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.80;

Mass data: 527 (M+H)⁺.

Example 16(48)6-(3-(2-carboxyethenyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 503 (M+H)⁺.

Example 16(49)6-(4-(2-nitroethenyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 504 (M+H)⁺.

Example 16(50)6-(3-phenylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.77;

Mass data: 509 (M+H)⁺.

Example 16(51)6-(4-(2-carboxyethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 505 (M+H)⁺.

Example 16(52)6-(3,5-difluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 937 (2M+H)⁺, 469 (M+H)⁺.

Example 16(53)6-(4-ethylthiophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.67;

Mass data: 985 (2M+H)⁺, 493 (M+H)⁺.

Example 16(54)6-(2-methoxy-5-(1-methylethyl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.73;

Mass data: 505 (M+H)⁺.

Example 16(55)6-(2-methylthiophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.55;

Mass data: 957 (2M+H)⁺, 479 (M+H)⁺.

Example 16(56)6-(2,4-difluorophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.58;

Mass data: 937 (2M+H)⁺, 469 (M+H)⁺.

Example 16(57)6-(2-methylcarbonylphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 949 (2M+H)⁺, 475 (M+H)⁺.

Example 16(58)6-(3-carboxyphenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.34;

Mass data: 953 (2M+H)⁺, 477 (M+H)⁺.

Example 16(59)6-(4-dimethylaminophenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.21;

Mass data: 951 (2M+H)⁺, 476 (M+H)⁺.

Example 16(60)6-(4-(thiophen-2-yl)phenyl)-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 871 (2M+H)⁺, 439 (M+H)⁺.

EXAMPLE 176-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a suspension of 60% sodium hydride (12 mg) in 1,4-dioxane (1.0 μL), asolution of 3,4-dimethoxybenzyl alcohol (25 mg) in 1,4-dioxane (1 mL)was dropped at room temperature. The mixture was stirred for 30 minutesat room temperature. A solution of the compound prepared in ReferenceExample 1 (41 mg) in 1,4-dioxane (1 mL) was added to the reactionmixture at room temperature. The mixture was stirred for 3 hours at 100°C. The reaction mixture was cooled to room temperature and concentrated.After the residue was washed with diisopropyl ether (5 mL), 1Nhydrochloric acid (1 mL) was added. The mixture was extracted withchloroform (3 mL) for two times. The extract was concentrated to givethe title compound (26 mg) having the following physical data.

TLC: Rf 0.47 (hexane:ethyl acetate=1:1);

NMR (d₆-DMSO): δ 11.06 (br, 1H), 7.91 (s, 1H), 7.84 (d, J=8.4 Hz, 2H),7.35 (d, J=8.4 Hz, 2H), 7.15 (d, J=1.8 Hz, 1H), 7.04 (dd, J=8.1, 1.8 Hz,1H), 6.95 (d, J=8.1 Hz, 1H), 5.28 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H),2.35 (s, 3H);

HPLC maintenance time (minutes): 4.10;

Mass data: 494 (M+H)⁺.

Example 17(1)-17(63)

The following compounds were obtained, using a corresponding alcoholcompound in stead of 3,4-dimethoxybenzyl alcohol, by the same procedureas a series of reactions of Example 17.

Example 17(1)2-((3-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.08;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺.

Example 17(2)2-((3-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.09;

Mass data: 390 (M+H)⁺.

Example 17(3)2-((3-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.98;

Mass data: 793 (2M+Na)⁺, 386 (M+H)⁺.

Example 17(4)6-bromo-2-((3-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.34;

Mass data: 448 (M+H)⁺.

Example 17(5)6-bromo-2-((3-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.34;

Mass data: 468 (M+H)⁺.

Example 17(6)6-bromo-2-((3-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 466 (M+H)⁺.

Example 17(7)6-bromo-2-((3-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.34;

Mass data: 502 (M+H)⁺.

Example 17(8)2-((2-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.99;

Mass data: 793 (2M+Na)⁺, 386 (M+H)⁺;

NMR (d₆-DMSO): δ 10.88 (s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.76 (d, J=9.0Hz, 2H), 7.49 (d, J=6.6 Hz, 1H), 7.38-7.31 (m, 3H), 7.05 (d, J=7.8 Hz,1H), 6.97 (td, J=7.8, 0.9 Hz, 1H), 5.38 (s, 2H), 3.01 (s, 3H), 2.36 (s,3H).

Example 17(9)2-(1-phenylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.04;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺;

NMR (d₆-DMSO): δ 10.94 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.66 (s, 2H),7.48 (d, J=7.2 Hz, 2H), 7.39-7.22 (m, 5H9, 6.12 (q, J=6.3 Hz, 1H), 2.36(s, 3H), 1.59 (d, J=6.3 Hz, 3H).

Example 17(10)2-((furan-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.82;

Mass data: 713 (2M+Na)⁺, 346 (M+H)⁺;

NMR (d₆-DMSO): δ 10.88 (s, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.80-7.73 (m,3H), 7.36 (d, J=8.1 Hz, 2H), 6.63 (d, J=3.0 Hz, 1H), 6.51-6.49 (m, 1H),5.35 (s, 2H), 2.36 (s, 3H).

Example 17(11)2-((2-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.06;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺.

Example 17(12)2-((2-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.10;

Mass data: 390 (M+H)⁺.

Example 17(13)6-bromo-2-((2-phenylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.45;

Mass data: 510 (M+H)⁺.

Example 17(14)2-((2-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.11;

Mass data: 869 (2M+Na)⁺, 424 (M+H)⁺.

Example 17(15)2-((naphthalen-1-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.15;

Mass data: 733 (2M+Na)⁺, 406 (M+H)⁺.

Example 17(16)2-((naphthalen-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.17;

Mass data: 833 (2M+Na)⁺, 406 (M+H)⁺.

Example 17(17)2-((2,3-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.95;

Mass data: 853 (2M+Na)⁺, 416 (M+H)⁺.

Example 17(18)2-((2,5-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.99;

Mass data: 853 (2M+Na)⁺, 416 (M+H)⁺.

Example 17(19)2-((3,5-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.97;

Mass data: 853 (2M+Na)⁺, 416 (M+H)⁺.

Example 17(20)2-((2,3-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 424 (M+H)⁺.

Example 17(21)2-((2,4-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.24;

Mass data: 424 (M+H)⁺.

Example 17(22)2-((2,5-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 424 (M+H)⁺.

Example 17(23)2-((2,6-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.19;

Mass data: 424 (M+H)⁺.

Example 17(24)2-((3,4-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 424 (M+H)⁺.

Example 17(25)2-((3,5-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.24;

Mass data: 424 (M+H)⁺.

Example 17(26)2-((4-ethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.17;

Mass data: 789 (2M+Na)⁺, 384 (M+H)⁺.

Example 17(27)2-((4-(1-methylethyl)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.26;

Mass data: 817 (2M+Na)⁺, 398 (M+H)⁺.

Example 17(28)2-((4-(1,1-dimethylethyl)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.35;

Mass data: 845 (2M+Na)⁺, 412 (M+H)⁺.

Example 17(29)2-((4-phenylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.26;

Mass data: 885 (2M+Na)⁺, 432 (M+H)⁺.

Example 17(30)2-((3-phenoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.26;

Mass data: 917 (2M+Na)⁺, 448 (M+H)⁺.

Example 17(31)2-((2-phenylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.00;

Mass data: 885 (2M+Na)⁺, 432 (M+H)⁺.

Example 17(32)2-((1,3-dioxaindan-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.95;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 17(33)2-((1,3-dioxaindan-5-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.93;

Mass data: 821 (2M+Na)⁺, 400 (M+H)⁺.

Example 17(34)2-((3-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.13;

Mass data: 869 (2M+Na)⁺, 424 (M+H)⁺.

Example 17(35)2-((4-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.08;

Mass data: 761 (2M+Na)⁺, 370 (M+H)⁺.

Example 17(36)2-((4-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.10;

Mass data: 801 (2M+Na)⁺, 390 (M+H)⁺.

Example 17(37)2-((4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.97;

Mass data: 793 (2M+Na)⁺, 386 (M+H)⁺.

Example 17(38)2-((4-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.13;

Mass data: 869 (2M+Na)⁺, 424 (M+H)⁺.

Example 17(39)6-bromo-2-((4-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 448 (M+H)⁺.

Example 17(40)6-bromo-2-((2-methylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.30;

Mass data: 448 (M+H)⁺.

Example 17(41)6-bromo-2-((2-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 468 (M+H)⁺.

Example 17(42)6-bromo-2-((2-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.26;

Mass data: 464 (M+H)⁺.

Example 17(43)6-bromo-2-((2-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.34;

Mass data: 502 (M+H)⁺.

Example 17(44)6-bromo-2-((naphthalen-1-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.37;

Mass data: 482 (M+H)⁺.

Example 17(45)6-bromo-2-((2,3-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.21;

Mass data: 494 (M+H)⁺.

Example 17(46)6-bromo-2-((4-ethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.43;

Mass data: 462 (M+H)⁺.

Example 17(47)6-bromo-2-((4-(1-methylethyl)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.50;

Mass data: 476 (M+H)⁺.

Example 17(48)6-bromo-2-((4-(1,1-dimethylethyl)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.55;

Mass data: 490 (M+H)⁺.

Example 17(49)6-bromo-2-((1,3-dioxaindan-4-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.19;

Mass data: 478 (M+H)⁺.

Example 17(50)6-bromo-2-((1,3-dioxaindan-5-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.17;

Mass data: 478 (M+H)⁺.

Example 17(5)6-bromo-2-((4-chlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.34;

Mass data: 468 (M+H)⁺.

Example 17(52)6-bromo-2-((4-methoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 464 (M+H)⁺.

Example 17(53)6-bromo-2-((4-trifluoromethylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.35;

Mass data: 502 (M+H)⁺.

Example 17(54)6-bromo-2-((naphthalen-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.41;

Mass data: 484 (M+H)⁺.

Example 1.7(55)6-bromo-2-((2,5-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 494 (M+H)⁺.

Example 17(56)6-bromo-2-((3,5-dimethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.22;

Mass data: 494 (M+H)⁺.

Example 17(57)6-bromo-2-((2,3-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.43;

Mass data: 502 (M+H)⁺.

Example 17(58)6-bromo-2-((2,4-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.45;

Mass data: 502 (M+H)⁺.

Example 17(59)6-bromo-2-((2,5-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.43;

Mass data: 502 (M+H)⁺.

Example 17(60)6-bromo-2-((2,6-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.45;

Mass data: 502 (M+H)⁺.

Example 17(61)6-bromo-2-((3,4-dichlorophenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.43;

Mass data: 502 (M+H)⁺.

Example 17(62)6-bromo-2-((4-phenylphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.50;

Mass data: 510 (M+H)⁺.

Example 17(63)6-bromo-2-((3-phenoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.46;

Mass data: 526 (M+H)⁺.

REFERENCE EXAMPLE 12

To a suspension of the compound (4) prepared in Reference Example 11(1.0 g) in dimethylsulfoxide (10 mL), triethylamine (0.948 mL),2-(trimethylsilyl)ethanol (0.487 mL) anddichlorobis(triphenylphosphine)palladium (II) (96 mg), successively,were added at room temperature. Under an atmosphere of carbon monoxidegas, the mixture was stirred for 24 hours at 80° C. The reaction mixturewas cooled to room temperature and filtered. The obtained resin waswashed with dimethylsulfoxide (30 mL) for three times, tetrahydrofuran(30 mL) for three times and methylene chloride (30 mL) for three times,and dried to give the compound (5) (1.03 g).

REFERENCE EXAMPLE 13

To a suspension of the compound (5) prepared in Reference Example 12(500 mg) in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride intetrahydrofuran solution (5 mL) was added to room temperature. Themixture was stirred for 1 hour at room temperature. The reaction mixturewas filtered. The obtained resin was washed with tetrahydrofuran (20 mL)for three times, a mixture of 0.2N hydrochloric acid and tetrahydrofuran(1:2)(20 mL) for three times, a mixture of water and tetrahydrofuran(1:2)(20 mL) for three times, tetrahydrofuran (20 mL) for three timesand methylene chloride (20 mL) for three times, and dried to give thecompound (6) (490 mg).

EXAMPLE 186-(perhydroazepin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a suspension of the compound (6) prepared in Reference Example 13(490 mg) in N,N-dimethylformamide (5 mL), homopiperidine (0.186 mL),N,N-diisopropylethylamine (0.575 mL) and hexafluorophosphoric acidbenzotriazol-1-yl-1-oxy-tris(pyrrolidino)phosphonium (859 mg) weresuccessively added. The mixture was stirred for 4 hours at roomtemperature. The reaction mixture was filtered. To a suspension of theobtained resin in N,N-dimethylformamide (5 mL), homopiperidine (0.186mL), N,N-diisopropylethylamine (0.575 mL), hexafluorophosphoric acidbenzotriazol-1-yl-1-oxy-tris(pyrrolidino)phosphonium (859 mg) wassuccessively added. The mixture was stirred for 16 hours at roomtemperature and the reaction mixture was filtered. The obtained resinwas washed with N,N-dimethylformamide (20 mL) for five times andmethylene chloride (20 mL) for five times. The title compound (167 mg)having the following physical data was obtained by the same procedure asa series of reactions of Example 14, using 50% solution oftrifluoroacetic acid in methylene chloride in stead of 50% solution oftrifluoroacetic acid in 1,2-dichloroethane.

TLC: Rf 0.66(chloroform:methanol=10:1);

NMR(d₆-DMSO): δ 8.57 (br, 1H), 8.49 (d, J=3.9 Hz, 1H), 7.65 (d, J=7.8Hz, 2H), 7.34 (m, 3H), 6.92 (d, J=7.8 Hz, 2H), 5.26 (s, 2H), 3.49 (m,4H), 2.37 (s, 3H), 1.60 (m, 4H), 1.41 (m, 4H);

HPLC maintenance time (minutes): 3.22;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(1)-18(77)

The following compounds were obtained, using a corresponding aminecompound in stead of homopiperidine, by the same procedure as a seriesof reactions of Example 18.

Example 18(1)6-cyclobutylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.26;

Mass data: 907 (2M+H)⁺, 454 (M+H)⁺.

Example 18(2)6-cyclopentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 935 (2M+H)⁺, 468 (M+H)⁺.

Example 18(3)6-cyclohexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(4)6-(5-methylisooxazol-3-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 961 (2M+H)⁺, 481 (M+H)⁺.

Example 18(5)6-(pyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.18;

Mass data: 907 (2M+H)⁺, 454 (M+H)⁺.

Example 18(6)6-(3-hydroxypyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.07;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(7)6-(1,3-thiazolin-2-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.14;

Mass data: 969 (2M+H)⁺, 485 (M+H)⁺.

Example 18(8)6-((tetrahydrofuran-2-yl)methyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.20;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(9)6-(4-methylpiperazin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.01;

Mass data: 965 (2M+H)⁺, 483 (M+H)⁺.

Example 18(10)6-(morpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.14;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(11)6-(thiomorpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.25;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(12)6-(pyridin-3-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.09;

Mass data: 953 (2M+H)⁺, 477 (M+H)⁺.

Example 18(13)6-(pyridin-4-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.10;

Mass data: 477 (M+H)⁺.

Example 18(14)6-(1,1-dimethylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.32;

Mass data: 456 (M+H)⁺.

Example 18(15)6-(1,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(16)6-(1-methyl-2-methoxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.20;

Mass data: 943 (2M+H)⁺, 472 (M+H)⁺.

Example 18(17)6-(1,3-dimethylbutyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.47;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(18)6-(1-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.31;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(19)6-(1-ethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(20)6-(1-methylbutyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(21)6-(2,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(22)6-(2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.09;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 18(23)6-(2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.29;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(24)6-(2-fluoroethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 891 (2M+H)⁺, 446 (M+H)⁺.

Example 18(25)6-(2-acetylaminoethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.09;

Mass data: 969 (2M+H)⁺, 485 (M+H)⁺.

Example 18(26)6-(2-methoxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 18(27)6-pentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(28)6-dimethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.12;

Mass data: 855 (2M+H)⁺, 428 (M+H)⁺.

Example 18(29)6-diethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.25;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(30)6-(N-methyl-N-propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.27;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(31)6-dipropylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.41;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(32)6-butylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.32;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(33)6-ethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 855 (2M+H)⁺, 428 (M+H)⁺.

Example 18(34)6-(3-hydroxypiperidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.09;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(35)6-(N-methyl-N-(2-methylpropyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.31;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(36)6-(N-methyl-N-pentylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.44;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(37)6-(N-methyl-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.25;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 18(38)6-(1-methylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.23;

Mass data: 883 (2M+H)⁺, 442 (M+H)⁺.

Example 18(39)6-(pyrazol-3-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.18;

Mass data: 931 (2M+H)⁺, 466 (M+H)⁺.

Example 18(40)6-(1,2,3,6-tetrahydropyridin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.27;

Mass data: 931 (2M+H)⁺, 466 (M+H)⁺.

Example 18(41)6-(pyrimidin-4-yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.22;

Mass data: 933 (2M+H)⁺, 478 (M+H)⁺.

Example 18(42)6-((1R)-1-hydroxymethyl-2-methylpropyl)aminocarbonyl-2-((pydin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.22;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(43)6-((1R)-1-methyl-2-hydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 18(44)6-(N-ethyl-N-(2-hydroxyethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.01;

Mass data: 943 (2M+H)⁺, 472 (M+H)⁺.

Example 18(45)6-(3-pyrrolin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.18;

Mass data: 903 (2M+H)⁺, 452 (M+H)⁺.

Example 18(46)6-(2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(47)6-(2-methylpiperidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(48)6-(3-methylpiperidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(49)6-(4-methylpiperidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.36;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(50)6-(1,1-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.39;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(51)6-(1-hydroxymethylpropylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 943 (2M+H)⁺, 472 (M+H)⁺.

Example 18(52)6-(2-methylbutylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(53)6-(2-dimethylaminoethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.00;

Mass data: 941 (2M+H)⁺, 471 (M+H)⁺.

Example 18(54)6-(2-hydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.07;

Mass data: 887 (2M+H)⁺, 444 (M+H)⁺.

Example 18(55)6-(2-propynyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.22;

Mass data: 875 (2M+H)⁺, 438 (M+H)⁺.

Example 18(56)6-(2-propenyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.22;

Mass data: 879 (2M+H)⁺, 440 (M+H)⁺.

Example 18(57)6-(3-methylbutyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.40;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(58)6-(3-dimethylaminopropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.01;

Mass data: 969 (2M+H)⁺, 485 (M+H)⁺.

Example 18(59)6-(3-ethoxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.23;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(60)6-hexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.51;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(61)6-(N,N-bis(2-propenyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.35;

Mass data: 959 (2M+H)⁺, 480 (M+H)⁺.

Example 18(62)6-(N-methyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.34;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(63)6-(N-ethyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(64)6-(N-methyl-N-hydroxyamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 859 (2M+H)⁺, 430 (M+H)⁺.

Example 18(65)6-(3-methoxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 943 (2M+H)⁺, 472 (M+H)⁺.

Example 18(66)6-(N-methyl-N-(2-dimethylaminoethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.00;

Mass data: 969 (2M+H)⁺, 485 (M+H)⁺.

Example 18(67)6-(N-ethyl-N-(1-methylethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.31;

Mass data: 939 (2M+H)⁺, 470 (M+H)⁺.

Example 18(68)6-(N-(1-hydroxyethyl)-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.05;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(69)6-((1S)-1-hydroxymethyl-2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.20;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(70)6-((2R)-2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.12;

Mass data: 967 (2M+H)⁺, 484 (M+H)⁺.

Example 18(71)6-((2R)-2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 18(72)6-((2S)-2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.11;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 18(73)6-(N-ethyl-N-methylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.18;

Mass data: 883 (2M+H)⁺, 442 (M+H)⁺.

Example 18(74)6-(2,2,2-trifluoroethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.33;

Mass data: 963 (2M+H)⁺, 482 (M+H)⁺.

Example 18(75)6-(N-(2-hydroxyethyl)-N-propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.05;

Mass data: 971 (2M+H)⁺, 486 (M+H)⁺.

Example 18(76)6-(N-methyl-N-(2-methoxyethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.16;

Mass data: 943 (2M+H)⁺, 472 (M+H)⁺.

Example 18(77)6-benzylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.38;

Mass data: 979 (2M+H)⁺, 490 (M+H)⁺;

NMR (d₆-DMSO): δ 11.60-11.20 (br, 1H), 9.10 (t, J=6.3 Hz, 1H), 8.80 (s,1H), 8.56 (d, J=3.6 Hz, 1H), 8.24 (s, 1H), 7.98 (dt, J=6.9, 1.8 Hz, 1H),7.89 (d, J=8.4 Hz, 2H), 7.45-7.08 (m, 8H), 5.61 (s, 2H), 4.48 (d, J=6.3Hz, 2H), 2.35 (s, 3H).

REFERENCE EXAMPLE 14

The compound (7) was obtained, using methanol in stead of2-(trimethylsilyl)ethanol, by the same procedure as a series ofreactions of Reference Example 12.

EXAMPLE 196-hydroxymethyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The compound (7) prepared in Reference Example 14 (400 mg) was added to2M lithium borohydride in tetrahydrofuran solution (2 mL) at roomtemperature. The mixture was stirred for 2 hours at room temperature.The reaction mixture was filtered. The obtained resin was washed withmethanol (3 mL) for five times, tetrahydrofuran (3 mL) for five timesand dichloroethane (3 mL) for five times. The title compound (41 mg)having the following physical data was obtained by the same procedure asa series of reactions of Example 14.

HPLC maintenance time (minutes): 3.07;

Mass data: 773 (2M+H)⁺, 387 (M+H)⁺.

EXAMPLE 206-methyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a suspension of the compound (4) prepared in Reference Example 11(300 mg) in anhydrous tetrahydrofuran (5 mL),[1,3-bis(diphenylphosphino)propane]dichloro nickel (II) (109 mg) wasadded at room temperature. The mixture was cooled to 0° C., and 0.93Mmethyl magnesium bromide in tetrahydrofuran solution (1.11 mL) was addedto the mixture. The mixture was stirred for 6 hours at room temperature.The reaction mixture was filtered. The obtained resin was washed withmethanol (5 mL) for five times and tetrahydrofuran (5 mL) for five timesand 1,2-dichloroethane (3 mL) for five times. The title compound (100mg) having the following physical data was obtained by the sameprocedure as a series of reactions of Example 14.

NMR(D₂O:CD₃CN=55:45): δ 8.50 (s, 1H), 8.40 (d, J=5.0 Hz, 1H), 7.89 (d,J=7.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.46 (s, 1H), 7.35 (dd, J=7.5,5.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 5.29 (s, 2H), 2.26 (s, 3H), 2.19(s, 3H);

HPLC maintenance time (minutes): 3.23;

Mass data: 741 (2M+H)⁺, 371 (M+H)⁺.

REFERENCE EXAMPLE 152-((3-(methoxymethyloxy)phenyl)methyloxy)-3-(N-(4-methylphenylsulfonyl)-N-(2-trimethylsilylethyl)amino)pyrazine

The title compound (843 mg) having the following physical data wasobtained, using the compound prepared in Example 3(4) (1.3 mg), by thesame procedure as a series of reactions of Reference Example 4.

TLC: Rf 0.75(hexane:ethyl acetate=1:1);

NMR(d₆-DMSO): δ 8.25 (d, J=2.7 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.69 (d,J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 7.11 (s,1H), 7.06 (d, J=7.5 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 5.40 (s, 2H), 5.19(s, 2H), 3.57-3.50 (m, 2H), 3.36 (s, 3H), 2.38 (s, 3H), 0.50-0.43 (m,2H), −0.14 (s, 9H).

REFERENCE EXAMPLE 162-((3-hydroxyphenyl)methyloxy)-3-(N-(4-methylphenylsulfonyl)-N-(2-trimethylsilylethyl)amino)pyrazine

To a solution of the compound prepared in Reference Example 15 (820 mg)in acetic acid (5.5 mL), water (5.5 mL) was added. The mixture wasstirred for 3 hours at 90° C. The reaction mixture was cooled to roomtemperature and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1) to give thetitle compound (756 mg) having the following physical data.

TLC: Rf 0.34(hexane:ethyl acetate=1:1);

NMR(CDCl₃): δ 8.25 (d, J=2.7 Hz, 1H), 8.14 (d, J=2.7 Hz, 1H), 7.69 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 6.85-6.82(m, 2H), 6.75-6.72 (m, 1H), 5.34 (s, 2H), 3.57-3.49 (m, 2H), 2.39 (s,3H), 0.50-0.40 (m, 2H), −0.14 (s, 9H).

EXAMPLE 212-((3-ethoxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

To a solution of the compound prepared in Reference Example 16 (30 mg)in tetrahydrofuran (2 mL), ethanol (0.011 mL), polymer supporttriphenylphosphine (1.34 mmol/g, 143 mg) and 40% diethylazodicarboxylate in toluene solution (0.087 mL) were successively addedat 0° C. The mixture was stirred for 18 hours at room temperature. Thereaction mixture was filtered. The obtained resin was washed withtetrahydrofuran (1 mL). 5N aqueous solution of sodium hydroxide (1 mL)was added to the mixture of the filtrate and the washings, and themixture was stirred for 30 minutes. After water (1 mL) was added to thereaction mixture, the mixture was extracted with chloroform (3 mL) fortwo times. The extract was dried over magnesium sulfate andconcentrated. 1.0M tetrabutylammonium fluoride in tetrahydrofuransolution (0.106 mL) was added to a solution of the obtained residue (23mg) in tetrahydrofuran (1.5 mL). The mixture was stirred for 17 hours atroom temperature. Water (1.5 mL) was added to the reaction mixture, andthe mixture was extracted with chloroform (3 mL) for two times. Theextract was dried over magnesium sulfate and concentrated to give thetitle compound (17 mg) having the following physical data.

TLC: Rf 0.73(hexane:ethyl acetate=1:1);

NMR(D₂O:CD₃CN=40:60, 50° C.): δ 7.80 (d, J=8.5 Hz, 2H), 7.59 (m, 2H),7.28 (d, J=8.5 Hz, 2H), 7.23 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.83 (d,J=8.0 Hz, 1H), 5.30 (s, 2H), 3.99 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.29(t, J=7.0 Hz, 3H);

HPLC maintenance time (minutes): 4.06;

Mass data: 799 (2M+H)⁺, 400 (M+H)⁺.

Example 21(1)-21(7)

The following compounds were obtained, using a corresponding alcoholcompound in stead of ethanol, by the same procedure as a series ofreactions of Example 21.

Example 21(1)2-((3-(1-methylethoxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.45;

Mass data: 827 (2M+H)⁺, 428 (M+H)⁺.

Example 21(2)2-((3-(2-methylpropyloxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 855 (2M+H)⁺, 428 (M+H)⁺.

Example 21(3)2-((3-butyloxyphenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.32;

Mass data: 855 (2M+H)⁺, 428 (M+H)⁺.

Example 21(4)2-((3-(4-methoxybutyloxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 4.10;

Mass data: 915 (2M+H)⁺, 458 (M+H)⁺.

Example 21(5)2-((3-(3-dimethylaminopropyloxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.42;

Mass data: 457 (M+H)⁺.

Example 21(6)2-((3-(tetrahydropyran-4-yloxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.95;

Mass data: 911 (2M+H)⁺, 456 (M+H)⁺.

Example 21(7)2-((3-(2-(piperidin-1-yl)ethyloxy)phenyl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

HPLC maintenance time (minutes): 3.47;

Mass data: 483 (M+H)⁺.

EXAMPLE 226-carboxy-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The compound (6) prepared in Reference Example 13 (110 mg) was added to1M tetrabutylammonium fluoride in tetrahydrofuran solution (1 mL). Themixture was stirred for 1 hour at room temperature. The reaction mixturewas filtered. The obtained resin was washed with tetrahydrofuran (3 mL)for five times and 1,2-dichloroethane (3 mL) for five times. The titlecompound (25 mg) having the following physical data was obtained by thesame procedure as a series of reactions of Example 14.

TLC: Rf 0.37(chloroform:methanol:acetic acid=9:1:0.5);

HPLC maintenance time (minutes): 3.14;

Mass data: 801 (2M+H)⁺, 401 (M+H)⁺;

NMR (d₆-DMSO): δ 8.72 (s, 1H), 8.51 (d, J=3.3 Hz, 1H), 8.03 (s, 1H),7.94 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.38 (dd, J=7.5, 4.8 Hz,1H), 7.11 (d, J=8.1 Hz, 2H), 5.29 (s, 2H), 2.27 (s, 3H).

EXAMPLE 236-methoxylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine

The title compound (120 mg) was obtained, using the compound (7)prepared in Reference Example 14 and 25% trifluoroacetic acid inmethylene chloride solution in stead of 50% trifluoroacetic acid in1,2-dichloroethane solution, by the same procedure as a series ofreactions of Example 14.

TLC: Rf 0.66(chloroform:methanol:acetic acid=9:1:0.5);

HPLC maintenance time (minutes): 3.23;

Mass data: 829 (2M+H)⁺, 415 (M+H)⁺;

NMR (CDCl₃): δ 8.71 (d, J=1.5 Hz, 1H), 8.62 (dd, J=4.8, 1.5 Hz, 1H),8.52 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.84 (dt, J=8.4, 1.8 Hz, 1H),7.37-7.26 (m, 3H), 5.48 (s, 2H), 3.94 (s, 3H), 2.41 (s, 3H).

Example 24(1)-24(114)

The following compounds were obtained, using a corresponding benzylalcohol in stead of 3,4-dimethoxybenzyl alcohol, and a correspondingsulfonyl chloride in stead of 4-chlorobenzensulfonyl chloride, by thesame procedure as a series of reactions of Reference Example 6→Example7.

Example 24(1)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,3-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.26;

Mass data: 492, 490, 488 (M+H)⁺.

Example 24(2)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-chloro-2-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.32;

Mass data: 472, 470, 468 (M+H)⁺.

Example 24(3)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-(trifluoromethyl)benzenesulfonamide

HPLC maintenance time (minutes): 4.17;

Mass data: 490, 488 (M+H)⁺.

Example 24(4)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-chlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.11;

Mass data: 458, 456, 454 (M+H)⁺.

Example 24(5)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-bromobenzenesulfonamide

HPLC maintenance time (minutes): 4.15;

Mass data: 502, 500, 498 (M+H)⁺.

Example 24(6)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-chloro-4-fluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.17;

Mass data: 476, 474, 472 (M+H)⁺.

Example 24(7)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dichloro-4-nitro-3-thiophenesulfonamide

HPLC maintenance time (minutes): 4.28;

Mass data: 543, 541, 539 (M+H)⁺, 317, 214.

Example 24(8)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,6-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.21;

Mass data: 492, 490, 488 (M+H)⁺.

Example 24(9)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-bromobenzenesulfonamide

HPLC maintenance time (minutes): 4.28;

Mass data: 502, 500, 498 (M+H)⁺.

Example 24(10)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4-difluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.12;

Mass data: 458, 456 (M+H)⁺.

Example 24(11)N-{5-bromo-3-[(6-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl}-4-methylbenzenesulfonamide

TLC: Rf 0.35 (hexane:ethyl acetate=2:1);

NMR(CDCl₃): δ 2.41 (s, 3H), 3.96 (s, 3H), 5.31 (s, 2H), 6.79 (d, J=8.5Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.49 (s, 1H), 7.66 (dd, J=8.5, 2.5 Hz,1H), 7.86 (s, 1H), 7.98 (d, J=8.5 Hz, 2H), 8.24 (d, J=2.5 Hz, 1H);

Mass data: 931 (2M+H)⁺, 467, 465 (M+H)⁺.

Example 24(12)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.15;

Mass data: 436, 434 (M+H)⁺.

Example 24(13)N-{5-bromo-3-[(2-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl}-4-methylbenzenesulfonamide

TLC: Rf 0.35 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 2.42 (s, 3H),3.99 (s, 3H), 5.37 (s, 2H), 6.92 (dd, J=7.0, 5.0 Hz, 1H), 7.30 (d, J=8.5Hz, 2H), 7.57 (s, 1H) 7.64 (dd, J=7.0, 2.0 Hz, 1H), 7.85 (s, 1H), 7.99(d, J=8.5 Hz, 2H), 8.20 (dd, J=5.0, 2.0 Hz, 1H);

Mass data: 467, 465 (M+H)⁺.

Example 24(14)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-chloro-4-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.30;

Mass data: 472, 470, 468 (M+H)⁺.

Example 24(15)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-chlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.19;

Mass data: 458, 456, 454 (M+H)⁺.

Example 24(16)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-fluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.04;

Mass data: 440, 438 (M+H)⁺.

Example 24(17)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,3,4-trichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.44;

Mass data: 528, 526, 524, 522 (M+H)⁺.

Example 24(18)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.30;

Mass data: 492, 490, 488 (M+H)⁺.

Example 24(19)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,6-difluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.00;

Mass data: 458, 456 (M+H)⁺.

Example 24(20)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-cyanobenzenesulfonamide

HPLC maintenance time (minutes): 4.00;

Mass data: 447, 445 (M+H)⁺.

Example 24(21)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-fluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.10;

Mass data: 440, 438 (M+H)⁺.

Example 24(22)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4,6-trichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.39;

Mass data: 528, 526, 524, 522 (M+H)⁺.

Example 24(23)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-thiophenesulfonamide

TLC: Rf 0.27 (toluene:ethyl acetate=15:1);

NMR(CDCl₃): δ 5.39 (s, 2H), 7.08 (dd, J=5.0, 4.0 Hz, 1H), 7.42 (m, 5H),7.61 (s, 1H), 7.63 (dd, J=5.0, 1.5 Hz, 1H), 7.91 (dd, J=4.0, 1.5 Hz,1H), 7.94 (s, 1H);

Mass data: (APCI, Pos. 40V) 428, 426 (M+H)⁺, 384, 382, 281, 279.

Example 24(24) N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]benzenesulfonamide

HPLC maintenance time (minutes): 4.06;

Mass data: 422, 420 (M+H)⁺.

Example 24(25)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-methyl-3-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.15;

Mass data: 481, 479 (M+H)⁺.

Example 24(26)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.13;

Mass data: 467, 465 (M+H)⁺.

Example 24(27)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dichloro-3-thiophenesulfonamide

TLC: Rf 0.49 (toluene:ethyl acetate=6:1);

NMR(CDCl₃): δ 5.42 (s, 2H), 7.33 (s, 1H), 7.43 (m, 5H), 7.71 (s, 1H),7.87 (s, 1H);

Mass data: (FAB, Pos.) 500, 498, 496, 494 (M+H)⁺.

Example 24(28)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-bromobenzenesulfonamide

HPLC maintenance time (minutes): 4.26;

Mass data: 502, 500, 498 (M+H)⁺.

Example 24(29)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.13;

Mass data: 436, 434 (M+H)⁺.

Example 24(30)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-bromo-2,5-difluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.26;

Mass data: 538, 536, 534 (M+H)⁺.

Example 24(31)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-(trifluoromethyl)benzenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 490, 488 (M+H)⁺.

Example 24(32)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-ethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.22;

Mass data: 450, 448 (M+H)⁺.

Example 24(33)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-1-benzothiophen-3-sulfonamide

HPLC maintenance time (minutes): 4.22;

Mass data: 478, 476 (M+H)⁺, 214.

Example 24(34)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-(trifluoromethoxy)benzenesulfonamide

HPLC maintenance time (minutes): 4.21;

Mass data: 506, 504 (M+H)⁺.

Example 24(35)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-methoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.08;

Mass data: 452, 450 (M+H)⁺.

Example 24(36)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-(trifluoromethyl)benzenesulfonamide

TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

NMR(d₆-DMSO): δ 5.37 (s, 2H), 7.38 (m, 3H), 7.52 (m, 2H), 7.93 (s, 1H),7.96 (d, J=8.0 Hz, 2H), 8.16 (d, J=8.0 Hz, 2H), 11.42 (s, 1H);

Mass data: 490, 488 (M+H)⁺.

Example 24(37)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4-dichloro-6-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.54;

Mass data: 506, 504, 502 (M+H)⁺.

Example 24(38)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-chloro-4-(trifluoromethyl)benzenesulfonamide

HPLC maintenance time (minutes): 4.37;

Mass data: 526, 524, 522 (M+H)⁺.

Example 24(39)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4,5-dichloro-2-thiophenesulfonamide

TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

NMR(CDCl₃): δ 55.40 (s, 2H), 7.42 (m, 5H), 7.65 (s, 1H), 7.68 (s, 1H),7.98 (s, 1H);

Mass data: (FAB, Pos.) 500, 498, 496, 494 (M+H)⁺.

Example 24(40)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-fluoro-2-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.19;

Mass data: 454, 452 (M+H)⁺.

Example 24(41)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-chloro-3-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.21;

Mass data: 503, 501, 499 (M+H)⁺.

Example 24(42)2-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)benzoic acidmethyl ester

HPLC maintenance time (minutes): 4.11;

Mass data: 480, 478 (M+H)⁺.

Example 24(43)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-1-benzothiophen-2-sulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 478, 476 (M+H)⁺, 214.

Example 24(44)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4,6-trimethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.39;

Mass data: 464, 462 (M+H)⁺.

Example 24(45)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.28;

Mass data: 492, 490, 488 (M+H)⁺.

Example 24(46)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-(trifluoromethoxy)benzenesulfonamide

HPLC maintenance time (minutes): 4.26;

Mass data: 506, 504 (M+H)⁺.

Example 24(47)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4,5-trichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.48;

Mass data: 528, 526, 524, 522 (M+H)⁺.

Example 24(48)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-methyl-2-(trifluoromethyl)-3-furansulfonamide

HPLC maintenance time (minutes): 4.30;

Mass data: 494, 492 (M+H)⁺, 214, 158.

Example 24(49)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-methoxy-4-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.08;

Mass data: 466, 464 (M+H)⁺.

Example 24(50)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-methoxy-2-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.11;

Mass data: 497, 495 (M+H)⁺.

Example 24(51)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.10;

Mass data: 467, 465 (M+H)⁺.

Example 24(52)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-chloro-2,5-dimethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.44;

Mass data: 486, 484, 482 (M+H)⁺.

Example 24(53)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dimethyl-3-thiophenesulfonamide

HPLC maintenance time (minutes): 4.22;

Mass data: 456, 454 (M+H)⁺, 265, 214.

Example 24(54)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-biphenylsulfonamide

HPLC maintenance time (minutes): 4.37;

Mass data: 498, 496 (M+H)⁺.

Example 24(55)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-methyl-5-nitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.15;

Mass data: 481, 479 (M+H)⁺.

Example 24(56)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-bromo-2-methoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.19;

Mass data: 532, 530, 528 (M+H)⁺.

Example 24(57)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,5-dimethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.26;

Mass data: 450, 448 (M+H)⁺.

Example 24(58)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-chloro-2-methoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.19;

Mass data: 488, 486, 484 (M+H)⁺.

Example 24(59)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-methoxybenzenesulfonamide

TLC: Rf 0.25 (hexane:ethyl acetate=4:1);

NMR(d₆-DMSO): δ 3.81 (s, 3H), 5.36 (s, 2H), 7.07 (d, J=9.0 Hz, 2H), 7.38(m, 3H), 7.53 (m, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.93 (s, 1H), 11.02 (s,1H);

Mass data: 452, 450 (M+H)⁺.

Example 24(60)4-acetyl-N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]benzenesulfonamide

HPLC maintenance time (minutes): 4.02;

Mass data: 464, 462 (M+H)⁺.

Example 24(61)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-phenoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.39;

Mass data: 514, 512 (M+H)⁺.

Example 24(62)3-[4-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)phenyl]propanoicacid methyl ester

HPLC maintenance time (minutes): 4.06;

Mass data: 508, 506 (M+H)⁺.

Example 24(63)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-cyanobenzenesulfonamide

HPLC maintenance time (minutes): 4.04;

Mass data: 447, 445 (M+H)⁺.

Example 24(64)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-(difluoromethoxy)benzenesulfonamide

HPLC maintenance time (minutes): 4.10;

Mass data: 488, 486 (M+H)⁺.

Example 24(65)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-isopropylbenzenesulfonamide

HPLC maintenance time (minutes): 4.32;

Mass data: 464, 462 (M+H)⁺.

Example 24(66)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(dimethylamino)-1-naphthalenesulfonamide

HPLC maintenance time (minutes): 3.95;

Mass data: 515, 513 (M+H)⁺.

Example 24(67)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-fluoro-3-methyl-1-benzothiophen-2-sulfonamide

HPLC maintenance time (minutes): 4.28;

Mass data: 510, 508 (M+H)⁺, 317, 214.

Example 24(68)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-cyanobenzenesulfonamide

TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

NMR(d₆-DMSO): δ 5.36 (s, 2H), 7.39 (m, 3H), 7.52 (m, 2H), 7.93 (s, 1H),8.05 (d, J=8.5 Hz, 2H), 8.10 (d, J=8.5 Hz, 2H), 11.55 (s, 1H);

Mass data: 447, 445 (M+H)⁺, 214.

Example 24(69)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-naphthalenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 472, 470 (M+H)⁺.

Example 24(70)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-(1,1-dimethylpropyl)benzenesulfonamide

HPLC maintenance time (minutes): 4.48;

Mass data: 492, 490 (M+H)⁺.

Example 24(71)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-chloro-3-methyl-1-benzothiophen-2-sulfonamide

HPLC maintenance time (minutes): 4.43;

Mass data: 528, 526, 524 (M+H)⁺, 317, 214, 158.

Example 24(72)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,3,5,6-tetramethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.46;

Mass data: 478, 476 (M+H)⁺.

Example 24(73)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dimethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 450, 448 (M+H)⁺.

Example 24(74)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-butoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.44;

Mass data: 494, 492 (M+H)⁺.

Example 24(75)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(5-chloro-1,2,4-thiadiazol-3-yl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.35;

Mass data: 548, 546, 544 (M+H)⁺, 317, 214, 158.

Example 24(76)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-tert-butylbenzenesulfonamide

HPLC maintenance time (minutes): 4.41;

Mass data: 478, 476 (M+H)⁺.

Example 24(77)5-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)-4-methyl-2-thiophenecarboxylicacid methyl ester

HPLC maintenance time (minutes): 4.13;

Mass data: 500,498 (M+H)⁺, 214.

Example 24(78)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(5-isoxazolyl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.08;

Mass data: 495, 493 (M+H)⁺, 214.

Example 24(79)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,3,4,5,6-pentamethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.50;

Mass data: 492, 490 (M+H)⁺.

Example 24(80)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-[2-(methylthio)-4-pyrimidinyl]-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 552, 550 (M+H)⁺, 214, 158.

Example 24(81)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-(methylsulfonyl)benzenesulfonamide

HPLC maintenance time (minutes): 3.86;

Mass data: 500, 498 (M+H)⁺.

Example 24(82)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-methoxy-2,3,6-trimethylbenzenesulfonamide

HPLC maintenance time (minutes): 4.39;

Mass data: 494, 492 (M+H)⁺.

Example 24(83)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-6-(dimethylamino)-2-naphthalenesulfonamide

HPLC maintenance time (minutes): 4.17;

Mass data: 515, 513 (M+H)⁺.

Example 24(84)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]4-(2-methoxyphenoxy)benzenesulfonamide

HPLC maintenance time (minutes): 4.28;

Mass data: 544, 542 (M+H)⁺.

Example 24(85)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2-methoxy-5-methylbenzenesulfonamide

HPLC maintenance time (minutes): 4.12;

Mass data: 466, 464 (M+H)⁺.

Example 24(86)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,4-dimethoxybenzenesulfonamide

HPLC maintenance time (minutes): 3.97;

Mass data: 482, 480 (M+H)⁺.

Example 24(87)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,5-dimethoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.02;

Mass data: 482, 480 (M+H)⁺.

Example 24(88)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(2-pyridinyl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.08;

Mass data: 505, 503 (M+H)⁺, 317, 214.

Example 24(89)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-chloro-1,3-dimethyl-1H-pyrazol-4-sulfonamide

HPLC maintenance time (minutes): 3.93;

Mass data: 476, 474, 472 (M+H)⁺, 317, 214.

Example 24(90)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.06;

Mass data: 495, 493 (M+H)⁺, 214.

Example 24(91)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonamide

HPLC maintenance time (minutes): 4.04;

Mass data: 504, 502, 500 (M+H)⁺, 317, 214.

Example 24(92)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(2-methyl-1,3-thiazol-4-yl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.17;

Mass data: 525, 523 (M+H)⁺, 214.

Example 24(93)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-methyl-1-phenylphenyl-1H-pyrazol-4-sulfonamide

HPLC maintenance time (minutes): 4.10;

Mass data: 502, 500 (M+H)⁺, 214.

Example 24(94)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-(1,3-oxazol-5-yl)-2-thiophenesulfonamide

HPLC maintenance time (minutes): 3.95;

Mass data: 495, 493 (M+H)⁺, 386, 384, 214.

Example 24(95)4-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicacid ethyl ester

HPLC maintenance time (minutes): 4.06;

Mass data: 511, 509 (M+H)⁺, 416, 414, 231, 214.

Example 24(96)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,4-dimethyl-1,3-thiazole-5-sulfonamide

HPLC maintenance time (minutes): 3.95;

Mass data: 457,455 (M+H)⁺, 214.

Example 24(97)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,5-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.41;

Mass data: 492, 490, 488 (M+H)⁺, 372, 370, 279, 214, 158.

Example 24(98)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,4-dichlorobenzenesulfonamide

HPLC maintenance time (minutes): 4.37;

Mass data: 492, 490, 488 (M+H)⁺, 317, 214, 158.

Example 24(99)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-chloro-4-fluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.22;

Mass data: 476, 474, 472 (M+H)⁺, 317, 214.

Example 24(100)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-fluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.11;

Mass data: 440, 438 (M+H)⁺, 279, 214.

Example 24(101)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,4-difluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.13;

Mass data: 458, 456 (M+H)⁺, 317, 214.

Example 24(102)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-2,3,4,5,6-pentafluorobenzenesulfonamide

HPLC maintenance time (minutes): 4.21;

Mass data: 512, 510 (M+H)⁺, 317, 214.

Example 24(103)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-methoxy-3,5-dinitrobenzenesulfonamide

HPLC maintenance time (minutes): 4.17;

Mass data: 542, 540 (M+H)⁺, 317, 214.

Example 24(104)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-propylbenzenesulfonamide

HPLC maintenance time (minutes): 4.37;

Mass data: 464, 462 (M+H)⁺, 279, 214.

Example 24(105)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-butylbenzenesulfonamide

HPLC maintenance time (minutes): 4.43;

Mass data: 478, 476 (M+H)⁺, 317, 214.

Example 24(106)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-4-isopropoxybenzenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 480, 478 (M+H)⁺, 214.

Example 24(107)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-(difluoromethoxy)benzenesulfonamide

HPLC maintenance time (minutes): 4.11;

Mass data: 488, 486 (M+H)⁺, 214.

Example 24(108)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,5-bis(trifluoromethyj)benzenesulfonamide

HPLC maintenance time (minutes): 4.37;

Mass data: 558, 556 (M+H)⁺, 317, 214, 158.

Example 24(109)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-bromo-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.22;

Mass data: 508, 506, 504 (M+H)⁺, 317, 214, 158.

Example 24(110)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-5-chloro-2-thiophenesulfonamide

HPLC maintenance time (minutes): 4.24;

Mass data: 464, 462, 460 (M+H)⁺, 317, 214, 158.

Example 24(111)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3,5-dimethyl-4-isoxazolesulfonamide

HPLC maintenance time (minutes): 4.06;

Mass data: 441, 439 (M+H)⁺, 317, 214.

Example 24(112)4-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)-5-(4-chlorophenyl)-2-methyl-3-furancarboxylicacid ethyl ester

HPLC maintenance time (minutes): 4.63;

Mass data: 610, 608, 606 (M+H)⁺, 214.

Example 24(113)5-({[3-(benzyloxy)-5-bromo-2-pyrazinyl]amino}sulfonyl)-2-methyl-3-furancarboxylicacid methyl ester

HPLC maintenance time (minutes): 4.06;

Mass data: 484, 482 (M+H)⁺, 317, 214.

Example 24(114)N-[3-(benzyloxy)-5-bromo-2-pyrazinyl]-3-thiophenesulfonamide

HPLC maintenance time (minutes): 3.99;

Mass data: 428, 426 (M+H)⁺, 214.

BIOLOGICAL EXAMPLES

It was demonstrated, for Example, by the following experiments that thecompound of the present invention of formula (I) has CCR4 antagonisticactivity, inhibitory activity for effector cell functions andTNFα-regulating activity, and shows efficacy in animal disease models.

All the procedures were conducted by conventionally used method on thebasis of basic biological methods. Furthermore, the measuring method ofthe present invention was modified to improve accuracy and/orsensitivity of the measurement for evaluating the compound of thepresent invention. The experimental method is explained in detail below.

Biological Example 1 Activity on Ca Ion Increase Stimulated by MDC

1-1: Isolation of Human CCR4 Gene

Human bone marrow cell cDNA was prepared using Marathon cDNAamplification kit (manufactured by Clontech). PCR primers hCCR4XbaI-F1(SEQ ID NO:1) and hCCR4XbaI-R1 (SEQ ID NO:2) were designed based on thesequence of GenBankX85740.

Using the human bone marrow cell cDNA as the template and using Ex Taq(manufactured by Takara), a PCR reaction (2 minutes at 95° C.→[30seconds at 95° C., 45 seconds at 60° C., 1 minute at 72° C.]×35 times)was carried out. The thus amplified PCR product was subjected to 1%agarose gel electrophoresis, purified using QIAquick Gel Extraction Kit(manufactured by QUIAGEN) and then digested with a restriction enzymeXbal. The digested fragments were ligated to an expression vectorpEF-BOS-bsr (Nucleic acid Research, 1990, Vol. 18, No. 17, p. 5322)using DNA Ligation Kit Ver. 2 (manufactured by Takara) and transformedinto Escherichia coli DH5a. By preparing the resulting plasmidpEF-BOS-bsr/hCCR4, its DNA sequence was identified.

1-2: Culturing of CHO Cell

CHO-dhfr(−) was cultured using Ham's F-12 (containing fetal bovine serum(10%), penicillin (100 U/mL) and streptomycin (100 μg/ml)). Also, thetransduced cell was cultured by adding blasticidin (5 μg/mL) to theabove medium.

1-3: Transduction into CHO Cell

The plasmid pEF-BOS-bsr/hCCR4 was transduced into the CHO-dhfr(−) cellusing a DMRIE-C reagent (manufactured by Gibco BRL). After 48 hours, themedium was replaced with a medium containing 5 μg/ml blasticidin tocarry out the selection, thereby establishing a stably overexpressingcell.

1-4: Inhibition Test on Activity of MDC Mediated by CCR4 (Activity ofMDC to Induce Transient Increase of Ca Ions).

The thus established human CCR4 stably overexpressing CHO cell (CCR4/CHOcell) was suspended in Ham's F-12 medium and FBS (10%) and dispensedinto a 96-well plate at 3.0×10⁴ cells/well. One day after culturing at37° C., the culture supernatant was discarded, and Ham's F-12 medium(containing Fura-2AM (5 μM), Probenecid (2.5 mM) and HEPES (20 mM; pH7.4)) was dispensed at 80 μL/well to carry out incubation for 1 hour at37° C. under shaded condition. After washing twice with 1×Hanks/HEPES(20 mM; pH 7.4) solution, the same solution was dispensed at 100μL/well. Each of the test compounds was added to the thusFura-2AM-incorporated CCR4/CHO cell, and 3 minutes thereafter, arecombinant human MDC (manufactured by PeproTach) diluted with1×Hanks/HEPES (20 mM; pH 7.4) solution was added thereto to a finalconcentration of 10 nM. Transient increase in the intracellular Ca²⁺concentration induced by the human MDC was measured using a Ca²⁺detector for 96-well (manufactured by Hamamatsu Photonics), andinhibition ratio (%) of the test compound was calculated by thefollowing equation:Inhibition ratio=[(Ec−Ea)/Ec]×100

-   -   Ec: measured value of Ca²⁺ transient increase by MDC; and    -   Ea: measured value of Ca²⁺ transient increase by MDC when a test        compound was added

Inhibition ratio for each concentration of the compound was calculated,and the value (IC₅₀ value) indicating 50% inhibition ratio wasdetermined from the inhibition curve.

As a result, the compounds of the invention showed an inhibition ratioof 50% or more at 10 μM. For Example, the compound of Example 1(1)showed an IC₅₀ value of 0.13 μM, and the compound of Example 1(2) showedan IC₅₀ value of 0.016 μM. Biological Example 2: Activity on cellmigration stimulated by MDC 2-1: Inhibition tests on MDC-induced T cellstrain (CCRF-CEM cell) migration A medium (0.3 mL) containing or free ofMDC (20 nM, manufactured by PeproTech) was added to the lower chamber of24-transwell plate, and further a medium (0.3 mL) containing a testcompound solution of 2-fold concentration (containing 0.02%dimethylsulfoxide (DMSO)) or a medium (0.3 mL) containing DMSO only wasadded thereto. To the upper chamber, CCRF-CEM cell suspension preparedin 1×10⁶ cells/50 μl and the test compound solution of 2-foldconcentration (0.05 m]L) were added. The test was initiated bysuperimpose the upper chamber on the lower chamber. The chambers wereincubated in a carbon gas incubator (5% CO₂, 95% humidity) kept at 37°C. for 4 hours, and the cells remaining in the upper chamber were suckedup and removed. Then, 0.1 ml of a buffer (phosphate-buffered saline(PBS) containing ethylenediamine tetra-acetate sodium (EDTA) (20 μM) wasadded thereto, and subjected- to reaction at 4° C. for 30 minutes. Thetranswell plate was centrifuged (1000 r.p.m.) for 5 minutes, and theincubation liquid (600 μL) in the lower chamber was collected, and thecell number was counted using Flow Cytometer (manufactured byBecton-Dickinson).

Migration inhibitory activity by the compound of the present inventionwas calculated by the following equation:Inhibition ratio(%)=[(A−B)/A]×100

-   -   A: Control value of the well to which the medium containing DMSO        and not containing test compound was added; and    -   B: Value of the well to which the medium containing DMSO and the        test compound was added Inhibition ratio for each concentration        of the compound was calculated, and the value (IC₅₀ value)        indicating 50% inhibition ratio was determined from the        inhibition curve.

As results, the compound of the present invention showed an inhibitionratio of 50% or more at 10 μM. For Example, the compound of Example 6(1)showed an IC₅₀ value of 0.01 μM.

Biological Example 3 Mouse Asthma Model

3-1: Mouse OVA-Induced Asthma Model

Ovalbumin (OVA, 0.2 mg/mL) and Alum (8 mg/mL) prepared in physiologicalsaline were intraperitoneally administered (500 μL) to the mouse (male,C57BL/6) on Day 1 (test starting day) and Day 8 (1 week thereafter), tosensitize the mouse. On Days 15 to 21, the mouse was taken to aninhalation chamber (W: 240 mm×L: 240 mm×H: 120 mm), and a 2% OVAsolution was sprayed with an ultrasonic wave type nebulizer (NE-U12,manufactured by Omron) for 20 minutes, to thus conduct induction. Thecompound of the present invention suspended in a medium, wasadministered orally at 30 minutes before OVA sensitization on Day 8 andat 30 minutes before OVA induction on Days 15 to 21. To the controlgroup was administered only the medium. Three hours after OVA inhalationon Day 21, the mouse was exsanguinated, the catheter tube was insertedinto the trachea, and the lung was washed with heparin-containingphysiological saline (10 U/ml), to give a bronchoalveolar lavage fluid(BALF). Leukocyte number in BALF was counted using hemocyte counter(SF-3000, manufactured by Sysmex).

As results, the compound of the present invention, for Example, thecompound of Example 1(3) suppressed leukocyte infiltration into the lungat a dose of 30 mg/kg.

Biological Example 4 Mouse Dermatitis Model

4-1: Mouse DTH Model

The mouse (male, Balb/c) was shaved on the abdomen with hair clippers,and to the abdomen was applied ethanol solution (100 μL) of 7% (w/v)2,4,6-trinitrochlrobenzene (TNCB), to sensitize the mouse. Seven daysafter sensitization, a 1% (w/v) TNCB solution in olive oil (20 μL) wasapplied to the auricle of the mouse (both sides of the right ear), toconduct induction. The present compound dissolved in a medium, wasapplied to both sides of the right ear (20 μL) 2 hours before applyingTNCB. To the control groups, was applied only the medium. Right afterthe administration of the compound and 24 hours after TNCB application,the thickness of the mouse auricle was measured with Dialthickness gauge(manufactured by Ozaki Seisakusho), which was used as indicator forefficacy in mouse DTH model.

As results, the compound of the present invention, for Example, thecompound of Example 6(1) suppressed the auricle swelling at aconcentration of 5%.

4-2: Mouse Dermatitis Model to which Hapten is Applied

To the auricle (both sides of the right ear) of the mouse (male,Balb/c), 1% (w/v) TNCB solution (acetone:olive oil=4:1) (20 μL) wasapplied to conduct first sensitization. Seven days after sensitization,1% (w/v) TNCB (acetone:olive oil=4:1) (20 μL) was applied to the mouseauricle, to conduct induction (Day 0). Furthermore, on Days 2, 4, 6, 8,10, 12, 14 and 16, the same procedure as on Day 0 was repeated. Thecompound of the present invention was dissolved in a medium, applied toboth sides of the right ear (20 μL) 2 hours before applying TNCB. To thecontrol groups, was applied only the medium. Right after theadministration of the compound and 24 hours after TNCB application, thethickness of the mouse auricle was measured with Dialthickness gauge(manufactured by Ozaki Seisakusho), which was used as indicator forefficacy in mouse dermatitis model to which hapten was continuouslyapplied.

As results, the compound of the present invention, for Example, thecompound of Example 1(3) suppressed the auricle swelling at aconcentration of 5%.

Experimental Example 5 Mouse TNFα Production Model

5-1: Mouse TNFα Production Model by LPS Stimulation

The present compound suspended in a medium, was orally applied to amouse (male, C57BL/6), and after 0.5 hour, lipipolysaccharide (LPS,055:B5, Sigma) was peritoneally administered to the mouse at a dose of60 mg/kg. To the control groups was orally applied only the medium.Sixty minutes after LPS treatment, heparin-added blood collection wasconducted from the abdominal vena cava under ether anesthesia, andcentrifuged (12,000 r.p.m.) at 4° C. for 3 minutes, to give the plasma.The thus obtained plasma sample was stored at −80° C. before use. TNFαin the plasma was quantified using an ELISA kit (R&D systems).

As results, the compound of the present invention, for Example, thecompound of Example 1(1) suppressed TNFα production by LPS stimulationat a dose of 100 mg/kg.

Formulation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4- 5.0 gmethylphenylsulfonylamino)pyrazine Carboxymethylcellulose calcium(disintegrating agent) 0.2 g Magnesium stearate (lubricating agent) 0.1g Microcrystalline cellulose 4.7 g

Formulation Example 2

The following components were admixed in conventional method. Thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freeze-dried to obtain 100 ampoules each containing 20mg of the active ingredient.6-bromo-2-((3,4-dimethoxyphenyl)methyloxy)-3-(4- 2.0 gmethylphenylsulfonylamino)pyrazine mannitol 20 g distilled water 500 ml

1. A compound of formula (I):

wherein ring A, ring B, and ring D each independently represents acyclic group which may be substituted; J represents a bond or a spacerhaving 1 to 8 atoms in its main chain; and G represents a bond or aspacer having 1 to 4 atoms in its main chain; or a salt thereof.
 2. Thecompound according to claim 1, wherein

wherein D^(J) and D^(G) each independently represents a carbon atom or anitrogen atom; and ---- represents a single bond or a double bond, andwhen ---- represents a double bond, D^(J) and D^(G) each represents acarbon atom.
 3. The compound according to claim 2, wherein ring D is acarbocyclic ring which may be substituted.
 4. The compound according toclaim 2, wherein ring D is a heterocyclic ring which may be substituted.5. The compound according to claim 4, wherein the heterocyclic ring is a3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ringhaving 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfuratoms as a hetero atom(s).
 6. The compound according to claim 2, wherein

wherein R^(D) represents a substituent of ring D; and M represents a 3-to 11-membered monocyclic or bicyclic cyclic group which may besubstituted.
 7. The compound according to claim 6, wherein

wherein R^(D) has the same meaning as described in claim
 6. 8. Thecompound according to claim 1, wherein ring A is a carbocyclic ringwhich may be substituted.
 9. The compound according to claim 1, whereinring A is a heterocyclic ring which may be substituted.
 10. The compoundaccording to claim 8, wherein the carbocyclic ring is a C3-15monocyclic, bicyclic or tricyclic carbocyclic ring.
 11. The compoundaccording to claim 9, wherein the heterocyclic ring is a 3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s).
 12. The compound according to claim 10, wherein thecarbocyclic ring is a benzene ring or a naphthalene ring.
 13. Thecompound according to claim 11 wherein the heterocyclic ring is apyridine ring, a pyrazole ring, a dioxaindane ring or a benzodioxanering.
 14. The compound according to claim 1, wherein ring B is acarbocyclic ring which may be substituted.
 15. The compound according toclaim 1, wherein ring B is a heterocyclic ring which may be substituted.16. The compound according to claim 14, wherein the carbocyclic ring isa C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring.
 17. Thecompound according to claim 15; wherein the heterocyclic ring is a 3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s).
 18. The compound according to claim 16, wherein thecarbocyclic ring is a C3-8 monocyclic carbocyclic ring.
 19. The compoundaccording to claim 17, wherein the heterocyclic ring is a 3- to8-membered monocyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1or 2 oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s). 20.The compound according to claim 18, wherein the carbocyclic ring is abenzene ring.
 21. The compound according to claim 19, wherein theheterocyclic ring is a pyridine ring or a thiophene ring.
 22. Thecompound according to claim 1, wherein J is a spacer having 1 to 8 atomsin its main chain and containing at least one oxygen atom.
 23. Thecompound according to claim 22, wherein the oxygen atom binds to ring D.24. The compound according to claim 22, wherein J is

wherein R³ and R⁴ each independently represents hydrogen or C1-8 alkyl;and E represents a bond or a spacer having 1 to 6 atoms in its mainchain.
 25. The compound according to claim 24, wherein R³ and R⁴ eachindependently represents hydrogen or methyl.
 26. The compound accordingto claim 24, wherein E is a bond,
 27. The compound according to claim24, wherein E is a spacer having 1 to 6 atoms in its main chain.
 28. Thecompound according to claim 27, wherein E is C1-4 alkylene or C1-3alkyleneoxy.
 29. The compound according to claim 28, wherein E ismethylene or methylenoxy.
 30. The compound according to claim 1, whereinG is a spacer having 1 to 4 atoms in its main chain and containing atleast one nitrogen atom.
 31. The compound according to claim 30, whereinG is —NR^(T1)—, —NR^(T1)—SO₂—, —NR^(T1)—CO—, —NR^(T1)—CO—NR^(T2)—,—NR^(T1)—SO₂—NR^(T2)—, —NR^(T1)—COO—, —NR^(T1)—O—, —NR^(T1)—NR^(T2)—,—NR^(T1)—W—, —SO₂—NR^(T1)—, —CO—NR^(T1)—, —OCO—NR^(T1)—, —O—NR^(T1)— orW—NR^(T1)—, wherein W represents a bivalent C1-3 aliphatic hydrocarbongroup which may be substituted; R^(T1) and R^(T2) each independentlyrepresents hydrogen, C1-8 alkyl which may be substituted, C2-8 alkenylwhich may be substituted, C2-8 alkynyl which may be substituted or a 3-to 8-membered cyclic group which may be substituted.
 32. The compoundaccording to claim 31, wherein G is —NH—SO₂—.
 33. The compound accordingto claim 1, wherein the compounds is a compound of formula (A):

wherein R¹ and R² each independently represents (1) hydrogen, (2) C1-8alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) halogen, (6) cyano, (7)nitro, (8) —CONR⁷R⁸, (9) —COOR⁹, (10) Cyc1 or (11) C1-8 alkylsubstituted with 1 to 5 groups selected from (a) —CONR⁷R⁸, (b) —COOR⁹,(c) —OR¹⁰, (d) —NR¹¹R¹², (e) halogen, and (f) Cyc1; or R¹ and R² aretaken together to represent C3-4 alkylene, —CH═CH—CH₂—, —CH₂—CH═CH—,—CH═CH—CH═CH— or —CH═CH—CH₂—CH₂—, wherein the carbocyclic ring to beformed may be substituted with C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl,C1-8 alkoxy, halogen, cyano, nitro or hydroxyl, wherein R⁷ and R⁸ eachindependently represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl,(4) C2-8 alkynyl, (5) Cyc2, (6) —OR¹³ or (7) C1-8 alkyl, C2-8 alkenyl orC2-8 alkynyl substituted with 1 to 5 groups selected from (a) —OR¹³, (b)—NR¹⁴R⁵, (c) —NR¹⁶COR¹⁷, (d) halogen, (e) CF₃, and (f) Cyc2; or R⁷ andR⁸ are taken together with the adjacent nitrogen atom to represent a 3-to 8-membered monocyclic heterocyclic ring having at least one nitrogenatom as a hetero atom(s) and 0 to 3 nitrogen atoms, 0 to 1 oxygen atomand/or 0 to 1 sulfur atom as an other hetero atom(s), wherein theheterocyclic ring may be substituted with (a) C1-8 alkyl, (b) halogen,(c) hydroxyl, or (d) C1-8 alkyl substituted with hydroxyl; R¹³ to R¹⁷each independently represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8alkenyl, (4) C2-8 alkynyl, (5) Cyc1, or (6) C1-8 alkyl, C2-8 alkenyl orC2-8 alkynyl substituted with Cyc1; R⁹ to R¹² each independentlyrepresents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8alkynyl, (5) Cyc1, or (6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with Cyc1; Cyc1 represents a C3-15 monocyclic, bicyclic ortricyclic carbocyclic ring or a 3- to 15-membered monocyclic, bicyclicor tricyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2oxygen atoms and/or 1 or 2 sulfur atoms as a hetero atom(s), whereinCyc1 may be substituted with 1 to 5 of R¹⁸; R¹⁸ represents (1) C1-8alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) cyano, (6)nitro, (7) trifluoromethyl, (8) trifluoromethoxy, (9) —OR¹⁹, (10) —SR²⁰,(11) —NR²¹R²², (12) —COR²³, (13) —COR²⁴, (14) —NR²⁵COR²⁶, (15)—CONR²⁷R²⁸, (16) Cyc2, or (17) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with 1 to 5 groups selected from (a) halogen, (b) cyano, (c)nitro, (d) trifluoromethyl, (e) trifluoromethoxy, (f) —OR¹⁹, (g) —SR²⁰,(h) —NR²¹R²², (i) —COR²³, (j) —COOR²⁴, (k) —NR²⁵COR²⁶, (l) —CONR²⁷R²⁸,and (m) Cyc2; R¹⁹ to R²⁸ each independently represents (1) hydrogen, (2)C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc2, or (6) C1-8alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2; Cyc2represents a C3-8 monocyclic carbocyclic ring or a 3- to 8-memberedmonocyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s), wherein Cyc2 maybe substituted with 1 to 5 of R²⁹; R²⁹ represents (1) C1-8 alkyl, (2)C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) cyano, (6) nitro, (7)hydroxyl, (8) trifluoromethyl, (9) trifluoromethoxy, or (10) —OR¹⁰⁰;R¹⁰⁰ represents C1-8 alkyl; R³ and R⁴ each independently representshydrogen or C1-8 alkyl; E¹ represents a bond or C1-6 alkylene, wherein acarbon atom in the alkylene group may be substituted with oxygen,sulfur, or —NR³⁰—; R³⁰ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3)C2-8 alkynyl, (4) phenyl, or (5) C1-8 alkyl substituted with phenyl;ring A¹ represents a C3-15 monocyclic, bicyclic or tricyclic carbocyclicring or a 3- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygen atomsand/or 1 or 2 sulfur atoms as a hetero atom(s); R⁵ represents (1) C1-8alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) cyano, (6)nitro, (7) trifluoromethyl, (8) trifluoromethoxy, (9) —OR³¹, (10)—NR³²R³³, (11) —NR³⁴COR³⁵, (12) Cyc3, or (13) C1-8 alkyl, C2-8 alkenylor C2-8 alkynyl substituted with 1 to 5 groups selected from (a)halogen, (b) cyano, (c) nitro, (d) trifluoromethyl, (e)trifluoromethoxy, (f) —OR³¹, (g) —NR³²COR³³, (h) —NR³⁴COR³⁵, and (i)Cyc3; R³¹ to R³⁵ each independently represents (1) hydrogen, (2) C1-8alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc3, or (6) C1-8 alkyl,C2-8 alkenyl or C2-8 alkynyl substituted with 1 to 5 groups selectedfrom (a) Cyc3, (b) —OR³⁶ and (c) —NR³⁷R³⁸; R³⁶ to R³⁸ each independentlyrepresents (1) hydrogen, (2) C1-8 alkyl, (3) —OR³⁹, or (4) —NR⁴⁰R⁴¹; R³⁹to R⁴¹ each independently represents hydrogen or C1-8 alkyl; Cyc3represents a C3-8 monocyclic carbocyclic ring or a 3- to 8-memberedmonocyclic heterocyclic ring having 1 to 4 nitrogen atoms, 1 or 2 oxygenatoms and/or 1 or 2 sulfur atoms as a hetero atom(s); ring B¹ representsa C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring or a 3- to15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms as ahetero atom(s); R⁶ represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8alkynyl, (4) halogen, (5) cyano, (6) nitro, (7) trifluoromethyl, (8)trifluoromethoxy, (9) —OR⁴², (10) —NR⁴³R⁴⁴, (11) —SR¹⁰¹, (12) —SO₂R²,(13) —COR¹⁰³, (14) —COOR¹⁰⁴, (15) Cyc2, or (16) C1-8 alkyl, C2-8 alkenylor C2-8 alkynyl substituted with 1 to 5 groups selected from (a)—COOR¹⁰⁴, (b) —NR¹⁰⁵COR¹⁰⁶, and (c) Cyc2; R⁴² to R⁴⁴ and R¹⁰¹ to R¹⁰⁶each independently represents (1) hydrogen, (2) C1-8 alkyl, (3) Cyc2, or(4) —COR¹⁰⁷, or (5) C1-8 alkyl substituted with 1 to 5 halogen atoms;R¹⁰⁷ represents C1-8 alkyl; and p and q each independently represents 0or an integer of 1 to
 5. 34. A prodrug for the compound according toclaim
 1. 35. A pharmaceutical composition which comprises the compoundof formula (I):

wherein ring A, ring B, and ring D each independently represents acyclic group which may be substituted; J represents a bond or a spacerhaving 1 to 8 atoms in its main chain; and G represents a bond or aspacer having 1 to 4 atoms in its main chain; or a salt thereof.
 36. Thepharmaceutical composition according to claim 35, which is a chemokinereceptor antagonist.
 37. The pharmaceutical composition according toclaim 36, wherein the chemokine receptor is CCR4.
 38. The pharmaceuticalcomposition according to claim 37, which is a preventive and/ortherapeutic agent for CCR4-mediated diseases.
 39. The pharmaceuticalcomposition according to claim 38, wherein the CCR4-mediated diseasesare inflammatory and/or allergic diseases, metabolism and/or endocrinesystem diseases, cancer diseases or infections.
 40. The pharmaceuticalcomposition according to claim 39, wherein the CCR4-mediated diseasesare inflammatory and/or allergic diseases.
 41. The pharmaceuticalcomposition according to claim 40, wherein the inflammatory and/orallergic diseases are respiratory diseases or dermatosis.
 42. Thepharmaceutical composition according to claim 41, wherein therespiratory diseases are asthma.
 43. The pharmaceutical compositionaccording to claim 41, wherein the dermatosis is atopic dermatitis. 44.A method for preventing and/or treating CCR4-mediated diseases in amammal, which comprises administering to a mammal an effective amount ofthe compound according to claim 1 or a salt thereof.
 45. Use of thecompound according to claim 1 or a salt thereof for the manufacture of apreventive and/or therapeutic agent for CCR4-mediated diseases.
 46. Apharmaceutical composition which comprises: a preventive and/ortherapeutic agent for CCR4-mediated diseases, which comprises thecompound according to claim 1 or a salt thereof as an active ingredient;and one or at least two medicaments selected from a bronchodilator drug,a steroid drug, a non-steroidal antiinflammatory drug, a leukotrienereceptor antagonist, a phosphodiesterase inhibitor, animmunosuppressant, an anti-allergic drug, a mediator-release inhibitor,an antihistamine drug, a metabolism promoter and/or a chemokineinhibitor.
 47. The pharmaceutical composition according to claim 35,which is an inhibitor of effector cell function.
 48. The pharmaceuticalcomposition according to claim 47, which is an inhibitor of cellmigration function.
 49. The pharmaceutical composition according toclaim 35, which is a TNFα regulator.